Received: 14 October 2019 Revised: 24 January 2020 Accepted: 28 January 2020
DOI: 10.1002/glia.23795
S P E C I A L I S S U E A R T I C L E
Functions of histone modifications and histone modifiers in
Schwann cells
Mert Duman1 | Margot Martinez-Moreno2 | Claire Jacob1 | Nikos Tapinos2
1Faculty of Biology, Institute of
Developmental Biology and Neurobiology, Abstract
Johannes Gutenberg University Mainz, Mainz, Schwann cells (SCs) are the main glial cells present in the peripheral nervous system
Germany
2 (PNS). Their primary functions are to insulate peripheral axons to protect them fromDepartment of Neurosurgery, Molecular
Neuroscience & Neuro-Oncology Laboratory, the environment and to enable fast conduction of electric signals along big caliber
Brown University, Providence, Rhode Island
axons by enwrapping them in a thick myelin sheath rich in lipids. In addition, SCs
Correspondence have the peculiar ability to foster axonal regrowth after a lesion by demyelinating
Claire Jacob, Institute of Developmental
and converting into repair cells that secrete neurotrophic factors and guide axons
Biology and Neurobiology, Johannes
Gutenberg University Mainz, Hanns-Dieter- back to their former target to finally remyelinate regenerated axons. The different
Hüsch-Weg 15, 55128 Mainz, Germany.
steps of SC development and their role in the maintenance of PNS integrity and
Email: cjacob@uni-mainz.de
regeneration after lesion are controlled by various factors among which transcription
Nikos Tapinos, Department of Neurosurgery,
factors and chromatin-remodeling enzymes hold major functions. In this review, we
Molecular Neuroscience & Neuro-Oncology
Laboratory, Brown University, Providence, RI. discussed how histone modifications and histone-modifying enzymes control SC
Email: nikos_tapinos@brown.edu
development, maintenance of PNS integrity and response to injury. The functions of
Funding information histone modifiers as part of chromatin-remodeling complexes are discussed in
International Foundation for Research in
another review published in the same issue of Glia.
Paraplegia, Grant/Award Number: P 174;
National Institutes of Health (NIH), Grant/
Award Number: 1R21CA235415-01A1; K E YWORD S
Warren Alpert Foundation development, histone modifications, histone modifiers, injury response, maintenance of PNS
integrity, regeneration, Schwann cells
1 | INTRODUCTION capacities. Satellite glia, which are very closely related to SCs and
found in dorsal root ganglia (DRG), and SCPs are generated twice dur-
Different cell types including Schwann cells (SCs), satellite glia, bound- ing development: the first wave at embryonic day (E)11 in mouse
ary cap cells, sensory neurons, chondrocytes, melanocytes, and embryos (Jacob et al., 2014) directly derives from neural crest cells
smooth muscle cells originate from neural crest cells (Jacob, 2015; and forms the SCPs of distal nerves and a subset of ventral root SCPs,
Woodhoo & Sommer, 2008). The first step of SC development is the while the second wave originates from boundary cap cells, themselves
specification of neural crest cells into SC precursors (SCPs), which will arising from neural crest cells, and forms the SCPs of dorsal roots and
later generate SCs and endoneurial fibroblasts in the peripheral ner- a subset of ventral root SCPs, satellite cells and DRG neurons (Maro
vous system (PNS; Jessen & Mirsky, 2005). In addition, recent work et al., 2004). SCPs further differentiate to become immature SCs
has shown that SCPs are capable to generate melanocytes, parasym- (at E13–E15 in mouse embryos), which encircle bundles of axons of
pathetic neurons, mesenchymal stem cells, and adrenal chromaffin different calibers and are also capable of producing factors that
cells (Kastriti et al., 2019), thereby demonstrating multipotency help to maintain their survival independently from axonal signals
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2020 The Authors. Glia published by Wiley Periodicals, Inc.
1584 wileyonlinelibrary.com/journal/glia Glia. 2020;68:1584–1595.
DUMAN ET AL. 1585
(Jessen & Mirsky, 2005). Around birth in mice, big caliber axons get Among those, cJun is a master inducer of the switch into the repair
sorted in a one-to-one relationship with SCs, which then wrap sorted phenotype (Arthur-Farraj et al., 2012; Gomez-Sanchez et al., 2015).
axons one-and-a-half times without producing myelin yet. During this Other factors such as Sox2 and Notch, which are negative regulators
process called radial sorting, immature SCs further differentiate into of SC myelination, are also involved in the regeneration process after
promyelinating SCs (Nave & Schwab, 2005). The last step of the matu- lesion (Gökbuget et al., 2015; Parrinello et al., 2010; Roberts et al.,
ration process leads to two different cell types: myelinating and non- 2017; Woodhoo et al., 2009; Wu et al., 2016).
myelinating SCs. Promyelinating SCs that have sorted big caliber In addition to transcription factors, a number of studies carried
axons further differentiate into myelinating SCs, which build a thick out in SCs have uncovered the critical roles of histone modifiers in
myelin sheath rich in lipids around axons, while non-myelinating SCs controlling SC development, plasticity and repair programs through
remain associated with bundles of small caliber axons and persist the regulation of transcription factor activity. Indeed, histone modifi-
throughout adulthood as Remak bundles (Jessen & Mirsky, 2005; cations change the architecture of chromatin by modulating the com-
Jessen, Mirsky, & Lloyd, 2015; Nave & Werner, 2014; Pereira, paction of nucleosomes; this regulates the accessibility of DNA for
Lebrun-Julien, & Suter, 2012; Salzer, 2015). transcription factors and the activation of their target genes, resulting
One of the unique aspects of the PNS is its capacity for regenera- in either activation or repression (Nocetti & Whitehouse, 2016;
tion. This is in large part due to the ability of SCs to convert into repair Strahl & Allis, 2000). In the histone code hypothesis, histone modifiers
cells to promote regeneration (Jessen & Mirsky, 2005, 2008; Jopling, are the writers of histone modifications and histone readers recognize
Boue, & Izpisua Belmonte, 2011). Traumatic injury of the PNS and loss and bind these modifications, which allows the recruitment of the
of axonal contact causes SCs to lose their differentiated morphology, transcriptional machinery to the readers binding sites and thereby
downregulate myelin genes, upregulate some markers of the imma- causes gene activation or repression. Among the many known histone
ture stage, and re-enter the cell cycle. At the same time, SCs convert readers, we can cite bromodomain proteins which bind acetylated his-
into repair cells that upregulate genes and secrete factors promoting tones, and chromobarrel and chromodomain proteins which bind
axon growth, neuronal survival, and macrophage invasion (Jessen & some lysine-methylated histones (reviewed in Musselman, Lalonde,
Mirsky, 2016). Morphologically, SCs transform into cells with long par- Côté, & Kutateladze, 2012). Histones can undergo various post-
allel processes that allow them to form regeneration tracks called translational modifications including, for the most described modifica-
bands of Büngner (Chen, Yu, & Strickland, 2007; Gordon et al., 2009; tions, methylation, acetylation, phosphorylation, ubiquitination,
Vargas & Barres, 2007), which help guide regenerating axons to their sumoylation, ADP ribosylation, and the less studied or recently identi-
original targets (Isaacman-Beck, Schneider, Franzini-Armstrong, & fied modifications biotinylation, citrullination, proline isomerization,
Granato, 2015). Finally, SCs re-differentiate into myelinating and non- crotonylation, lysine 2-hydroxyisobutyrylation, glutamine 5 sero-
myelinating SCs that envelop the regenerated axons to either re- tonylation, lysine benzoylation (Andrews, Strahl, & Kutateladze, 2016;
myelinate them or to re-build Remak bundles in association with small Zhao, Yue, Li, & Li, 2019). Acetylation, ubiquitination, sumoylation,
caliber axons. biotinylation, and crotonylation occur exclusively on lysine
There are many transcription factors involved in SC developmen- (K) residues, whereas methylation can occur on all three basic amino
tal process, SC plasticity and regenerative capacity after lesion (Jacob, acids lysine, arginine (R) and histidine, although methylation of histi-
2015, 2017; Jessen & Mirsky, 2019a, 2019b; Sock & Wegner, 2019; dine residues is rare. Phosphorylation occurs on serine and threonine,
Stierli, Imperatore, & Lloyd, 2019; Svaren & Meijer, 2008). Among ADP ribosylation on arginine, aspartic acid and glutamine, and cit-
those, the promyelinating factors Sox10, Oct6, and Krox20 (also rullination converts arginine residues into citrulline. Acetylation and
known as Egr2) have major functions in the myelination and methylation are the modifications that have been the most frequently
remyelination processes (Weider & Wegner, 2017). Sox10 is studied and that have been reported in SCs. This review will thus
expressed in neural crest cells and is required for each step of SC thereafter focus on the functions of these modifications in SC biology.
development, for the maintenance of PNS integrity and for
remyelination after lesion (Bremer et al., 2011; Britsch et al., 2001;
Finzsch et al., 2010; Frob et al., 2012; Jessen & Mirsky, 2005; 2 | HISTONE ACETYLTRANSFERASES
Kuhlbrodt, Herbarth, Sock, Hermans-Borgmeyer, & Wegner, 1998; (KATS) AND HISTONE DEACETYLASES
Paratore, Goerich, Suter, Wegner, & Sommer, 2001). Sox10 has the (HDACS)
ability to upregulate its own expression and induces the expression of
Oct6, which plays an important role in the differentiation process KATs (also known as HATs) are enzymes that add acetyl groups to
from promyelinating to myelinating cells (Bermingham Jr. et al., 1996; lysine residues of histone tails, which leads to less condensed chroma-
Jaegle et al., 1996); Sox10 and Oct6 together activate the expression tin and promotes the access for the transcriptional machinery. HDACs
of Krox20, which in turn activates the expression of myelin genes are chromatin-remodeling enzymes that can remove acetyl groups
together with Sox10 and is thus essential for myelination (Ghislain from histone tails (de Ruijter, van Gennip, Caron, Kemp, & van
et al., 2002; Kuhlbrodt et al., 1998; Topilko et al., 1994). After an Kuilenburg, 2003; Jacob, 2017; Michan & Sinclair, 2007). Removal of
injury, a different set of transcription factors controls SC demyelin- acetyl groups leads to locally more condensed chromatin that limits or
ation and conversion into repair cells (Jessen & Arthur-Farraj, 2019). selects DNA access for the transcriptional machinery. KATs and HDACs
1586 DUMAN ET AL.
are thus able to control transcriptional activity (Hodawadekar & residues and among them, some have been shown or proposed to
Marmorstein, 2007). KATs are known as transcriptional co-activators, also demethylate arginine residues (Walport et al., 2016; Zhang, Jing,
whereas HDACs are mostly described to act as transcriptional corepres- Li, He, & Guo, 2019).
sors, although several studies have shown that HDACs can also partici-
pate to transcriptional activation (Greer et al., 2015; Jacob, 2017; Wang
et al., 2009). KATs and HDACs do not bind DNA directly, they thus 4 | FUNCTIONS OF HISTONE
need a DNA binding partner, such as a transcription factor, to modify MODIFICATIONS AND HISTONE MODIFIERS
histones. In addition to modifying histones, KATs and HDACs can acet- IN SC DEVELOPMENT
ylate and deacetylate other targets including several transcription fac-
tors, and can thereby control the activity of these transcription factors 4.1 | Acetylation and deacetylation
(Deckert & Struhl, 2001; Greer et al., 2015; Jacob et al., 2014; Jacob,
Lebrun-Julien, & Suter, 2011; Wang et al., 2009). There are several fam- HDAC1 and HDAC2 (HDAC1/2) have key functions during SC devel-
ilies or classes of KATs and HDACs. KATs are subdivided into five opment, in the maintenance of PNS integrity and in the remyelination
different families: Gcn5-related acetyltransferases (GNATs), the MYST process after lesion. These two class I HDACs are highly homologous
(for MOZ, Ybf2/Sas3, Sas2 and Tip60)-related KATs, p300/CBP KATs, and can efficiently compensate for the loss of each other. For this rea-
the general transcription factor KATs, and the nuclear hormone-related son, the ablation of HDAC1 or of HDAC2 often does not lead to any
KATs (Carrozza, Utley, Workman, & Côté, 2003; Torchia, Glass, & obvious phenotype or only to a mild transient phenotype (Jacob,
Rosenfeld, 1998). HDACs are subdivided into four different classes: the Christen, et al., 2011), and ablation of both HDACs is usually neces-
classical HDACs constituted by Class I, Class II, and Class IV HDACs, sary to identify their functions. HDAC1/2 are highly expressed during
which need Zn2+ to be active, and Class III HDACs that are NAD+- SC specification and are upregulated again soon after birth in SCs of
dependent (de Ruijter et al., 2003; Jacob, Lebrun-Julien, & Suter, mouse peripheral nerves (Jacob et al., 2014; Jacob, Christen, et al.,
2011). There are 18 known mammalian HDACs: HDAC1, 2, 3, and 2011). HDAC1/2 levels remain high during the active phase of devel-
8 belong to Class I, HDAC4, 5, 6, 7, 9, and 10 are Class II HDACs, opmental myelination and decrease when the myelination process is
HDAC11 is the only member of the Class IV, and Class III is constituted complete to remain expressed at low but steady levels during adult-
by seven sirtuins. hood (Jacob, Christen, et al., 2011). We showed that HDAC1/2 are
required for the specification of neural crest cells into SC precursors.
Indeed, conditional ablation of HDAC1/2 in neural crest cells by
3 | HISTONE METHYLTRANSFERASES crossing Hdac1 and Hdac2 floxed mice with mice expressing the Cre
AND HISTONE DEMETHYLASES recombinase under the Wnt1 promoter leads to the absence of
peripheral glia specification and strongly reduced Sox10 and Pax3
Lysine methyltransferases and arginine methyltransferases (KMTs and expression (Jacob et al., 2014). In this study, we demonstrate that
PRMTs, respectively; also known as HMTs) are enzymes that catalyze HDAC1/2 interact with Sox10 to activate the promoter of Pax3,
the addition of methyl groups to target residues of histone tails, while another key transcription factor for SC specification (Auerbach, 1954;
histone demethylases (KDMs for lysine demethylases; also known as Franz, 1990; Olaopa et al., 2011). In turn, Sox10 and Pax3 activate
HDMs) remove these methyl groups from target residues. The out- together the Sox10MCS4 enhancer (also called U3 enhancer) to main-
come of histone methylation depends on the location of the target tain high Sox10 levels necessary for inducing the expression of the
amino acid and in the case of arginine methylation on the exact posi- early determinants of the SC lineage Fatty acid binding protein
tion of the methyl group on the target residue (Dieker & Muller, 2010; 7 (Fabp7) and Myelin protein zero (P0). While Sox10 seems to indi-
Jenuwein & Allis, 2001; Tsai & Casaccia, 2019). Histone methylation rectly activate the Fabp7 promoter, HDAC1/2, Sox10, and Pax3 are
marks associated with transcriptional activation are located on H3K4, recruited to the P0 promoter to induce its activation and the expres-
H3K36, H3K79, H3R17, H3R26, and H3R42 (recently identified, sion of P0 (Jacob et al., 2014). HDAC1/2 also hold critical functions
Casadio et al., 2013), whereas repressive methylation marks are later in development during the myelination process, as shown by
located on H3K9, H3K27, H3K64 (recently identified, Lange et al., radial sorting delay, absence of myelin and massive SC apoptosis in
2013), H4K20 and H3R8. Methylation of H3R2 and H4R3 can also mouse mutants where HDAC1/2 have been deleted in SCs after the
occur and leads to either transcriptional activation or repression specification of the lineage by crossing Hdac1/2 floxed mice with mice
depending on the enzyme that adds the methyl groups to the arginine expressing the Cre recombinase under control of the Dhh promoter
residue (Pattaroni & Jacob, 2013). Methyltransferases are subdivided (Jacob, Christen, et al., 2011). Interestingly, this work allowed to iden-
into three families: the SET-domain-containing proteins and tify specific primary functions for HDAC1 and HDAC2: while HDAC1
DOT1-like proteins that methylate lysine residues, and the protein maintains SC survival in early postnatal SCs by preventing precocious
arginine N-methyltransferases that methylate arginine residues. increase of active beta-catenin levels, HDAC2 acts together with
KDMs are classified into two families, the amine oxidases and the Sox10 to activate the transcription of Sox10, Krox20 and P0 and
Jumonji C (JmjC) domain-containing proteins (Pattaroni & Jacob, thereby induces the myelination program (Jacob, Christen, et al.,
2013). These two families of demethylases demethylate lysine 2011). In a similar study, Chen et al. (2011) show that the absence of
DUMAN ET AL. 1587
HDAC1/2 prevents SC developmental myelination and leads to low in the SC myelination process (Deng et al., 2017; Fernando et al.,
Sox10 expression in SCs, consistent with the study published by 2016; Grove et al., 2017; Poitelon et al., 2016).
Jacob, Christen, et al. (2011). However, in contrast to the study of
Jacob, Christen, et al. (2011), the study of Chen et al. (2011) does not
identify a major SC apoptosis phenotype in the absence of HDAC1/2 4.2 | Methylation and demethylation
and proposes a different mechanism of action of HDAC1/2 in SC
myelination. Indeed, Chen et al. (2011) report that HDAC1/2 interact Histone methylation enzymes also have critical functions in the devel-
with NFkB to activate the Sox10 promoter and thereby induce mye- opment of the nervous system (Pattaroni & Jacob, 2013). In the con-
lination. A third study (Morton et al., 2013) demonstrates however text of the present review, Strobl-Mazzulla, Sauka-Spengler, and
that activation of NFkB in SCs is dispensable for in vivo myelination, Bronner-Fraser (2010) demonstrated that the H3K9 demethylase
suggesting that the action of HDAC1/2 in promoting NFkB activity is JMJD2A is essential for the specification of neural crest cells in chick
likely to have minor functions in the myelination process. embryos. Indeed, loss of JMJD2A causes depletion of neural crest
The functions of other HDACs including HDAC3 and HDAC4 specifier genes including Sox10, Slug (also known as Snail2), Wnt1,
have also been investigated in SCs. The first study on HDAC3 shows FoxD3, and Sox8. Chromatin immunoprecipitation analyses show that
that HDAC3 forms a transcriptional repressor complex together with H3K9me3 marks regulate neural crest specifier gene expression and
HDAC1, HDAC2, and SC factor 1/positive regulatory domain protein that JMJD2A binds to regulatory regions of these genes (Strobl-
4 (SC1/PRDM4), a p75NTR-interacting zinc finger protein (Chittka Mazzulla et al., 2010). In this study, Strobl-Mazzulla et al. (2010) also
et al., 2004). This complex represses Cyclin E transcription through the show that in neural crest cells Sox10 and Slug gene bodies are marked
binding of SC1/PRDM4 to the Cyclin E promoter and causes cell pro- by H3K36 methylation, which is a mark of actively transcribed genes.
liferation arrest (Chittka et al., 2004). More recently, Gomis-Coloma NSD3 is a H3K36 methyltransferase that catalyzes mono- and
et al. (2018) reported that cAMP activates the shuttling of HDAC4 dimethylation of H3K36 and also promotes H3K36 trimethylation in
from the cytoplasm to the nucleus of SCs. HDAC4 then binds to the gene bodies (Rahman et al., 2011). Jacques-Fricke and Gammill (2014)
cJun promoter and prevents the expression of cJun by recruiting the report that NSD3 knockdown in chick embryos during neural crest
repressor complex NCoR1/HDAC3, thereby allowing SC differentia- specification impairs expression of Sox10 and Slug, and also of the
tion and myelin gene expression. The inhibitor of SC myelination cJun neural plate border gene Msx1 and the neural crest transcription fac-
is known to antagonize Krox20 expression (Parkinson et al., 2008). tors Sox9 and FoxD3. Specification of neural crest cells also requires
Gomis-Coloma et al. (2018) show that expression of constitutively H3K4 methylation, as shown by impaired expression of the neural
active HDAC4 can on its own induce the expression of Krox20 and crest specifier genes FoxD3, Slug, and Twist upon knockdown in
myelin genes. These findings suggest that HDAC3 contributes to pro- Xenopus laevis of KMT2D, a KMT catalyzing H3K4 mono-, di-, and
mote the SC differentiation and myelination processes. However, this trimethylation (Schwenty-Lara, Nehl, & Borchers, 2019).
appears somewhat in contradiction with the studies of Rosenberg In comparison to the specification of neural crest cells, the func-
et al. (2018) and He et al. (2018) showing a hypermyelination pheno- tions of histone methylation enzymes in the specification of SC pre-
type when HDAC3 is ablated in SCs. Discrepancies also exist in the cursors has been a lot less described, except for the KMT EZH2,
HDAC3 mechanism of action proposed in the two latter studies: while which catalyzes the trimethylation of H3K27, a repressive methylation
Rosenberg et al. (2018) report that HDAC3 allows the switch from mark, which, however, does not appear to be required for the specifi-
developmental myelination to a homeostasis program that maintains cation of neural crest cells into SC precursors (Schwarz et al., 2014).
myelination in adults, the work of He et al. (2018) indicates that Later in the developmental process, EZH2 has been reported to be
HDAC3 directly antagonizes the myelination program. The functions necessary for SC maturation and myelin gene expression in culture
of HDAC3 will therefore need to be further clarified by additional (Heinen et al., 2012). In this study, Heinen et al. (2012) show that
studies. EZH2 inactivates the promoter of p75kip2 by H3K27me3 marks,
In summary, HDACs are key enzymes for SC development. His- which prevents the expression of p75kip2 and p75kip2-dependent
tone acetylation also seems to play a role in the SC developmental expression of Hes5 (Heinen et al., 2012), a transcriptional repressor
process. Indeed, Lopez-Anido et al. (2016) have shown that major of myelin genes (Liu et al., 2006). However, the function of
enhancer regions of the myelin gene Pmp22, which is highly expressed EZH2-mediated H3K27 methylation in SCs does not seem critical for
in SCs, are marked by H3K27 acetylation (H3K27Ac) before birth in SC myelination in vivo. Indeed, the study of Ma et al. (2015) reports
mouse peripheral nerves. These H3K27Ac marks prime the Pmp22 that ablation of the PRC2 subunit Eed in SCs by crossing floxed Eed
gene for its subsequent activation by transcription factors including and P0-Cre mouse lines, which inactivates the PRC2 complex and thus
Sox10 and Krox20. In addition, binding motives for the TEA domain prevents EZH1/EZH2-mediated H3K27me3, does not affect develop-
(Tead) family of transcription factors are localized in enhancer regions mental myelination and instead causes hypermyelination at the adult
of Pmp22 which are marked by H3K27Ac, and Tead1 activates Pmp22 stage. In this study, the authors show that inactivation of the PRC2
enhancers (as well as the Krox20 gene) together with the co-activators complex results in impaired repression of the Igfbp2 promoter, subse-
Yap and Taz (Grove et al., 2017; Lopez-Anido et al., 2016), which have quently leading to increased expression of Igfbp2, which promotes
been shown by several independent groups to hold critical functions Akt-dependent myelination. Alternatively or in addition, since
1588 DUMAN ET AL.
Neuregulin (NRG)1 Type 1 is a strong activator of the myelination PRC2 complex (Ma et al., 2015), one of the two Polycomb repressor
process (Stassart et al., 2013), this hypermyelination phenotype could complexes (the other one being PRC1). The PRC2 complex is required
be due to increased expression of NRG1 Type 1 observed at 2 months for initial targeting of genomic regions (PRC Response Elements or
of age in SCs of Eed mutant mice (Ma, Duong, Moran, Junaidi, & PRE), while the PRC1 complex is required for stabilizing gene silencing
Svaren, 2018). and underlies cellular memory of the silenced region (Veneti,
H3K27me3 marks have other important functions during SC mat- Gkouskou, & Eliopoulos, 2017). EZH2, one of the two KMTs that can
uration: nuc-ErbB3, an alternative transcript from the ErbB3 locus be found in the PRC2 complex, catalyzes the di- and tri-methylation
which binds to a specific DNA motif, has been shown to control of H3K27. In adult SCs, these histone methylation marks are enriched
H3K27 methyltransferase activity and total levels of H3K27me3 at promoters of genes associated with injury response (Ma et al.,
(Ness et al., 2016). Inactivation of nuc-ErbB3 by a point mutation dis- 2015), thereby preventing inappropriate expression of injury-induced
abling its nuclear localization but preserving the function of the ErbB3 genes.
receptor causes sciatic nerve hypermyelination during postnatal Acetylation of H3K27, a marker of active promoters and distal
development and correlates with loss of H3K27me3 marks on the gene enhancers (Ernst et al., 2011), has been found to mark active
promoters of genes including Sox10 and Hdac1, and thus with the de- enhancers of Krox20 and Sox10 during myelin maintenance (Hung,
repression of these genes (Ness et al., 2016), likely promoting Sun, Keles, & Svaren, 2015), suggesting a function of H3K27Ac in
myelination. maintaining appropriate levels of Krox20 and Sox10 in adults. HDACs
also play a role in PNS myelin maintenance. For instance, HDAC1/2,
which are expressed at low but steady levels in adult SCs, have critical
5 | FUNCTIONS OF HISTONE functions in maintaining the structure of the paranodes and nodes of
MODIFICATIONS AND HISTONE MODIFIERS Ranvier by modulating the expression of P0. In this case, HDAC1/2
IN THE MAINTENANCE OF PNS INTEGRITY most likely act as co-factors of the transcription factor Sox10 to acti-
vate the P0 promoter (Brügger et al., 2015), leading to maintained
The continuous dialog between axons and glial cells is fundamental expression of P0. Ablation of HDAC1/2 in adult SCs leads to the
for myelin formation during development, myelin maintenance and decrease of P0 expression by 50% and to motor and sensory loss of
remyelination after nerve injury. In disease, axon damage is observed function. These findings are paralleled by severe disruption of para-
after myelin damage, suggesting disturbed glia–axon signaling nodes and nodes of Ranvier, while myelination is mildly affected. In
(Nave & Trapp, 2008). Krox20 in SCs is considered, together with addition to ensuring the cohesion between two adjacent myelin lamel-
Sox10, as a master transcription factor for initiation, regulation, and lae through its homophilic adhesion properties, P0 also maintains the
maintenance of peripheral myelination (Topilko et al., 1994). An imbal- stability of the paranodal and nodal complexes through interaction
ance of Krox20 expression results in demyelination or hyper- with neurofascins (Brügger et al., 2015). Although HDAC1/2 hold crit-
myelination that jeopardizes the stability and function of axons. ical functions in the maintenance of the PNS integrity, their expres-
During myelination, axonal NRG1 Type III regulates the expression of sion levels are low as compared to the active phase of myelination
Krox20 and Sox10 in SCs (Bremer et al., 2011; Pereira et al., 2012), during postnatal development (Jacob, Christen, et al., 2011). Rosen-
while the continuous expression of Krox20 and Sox10 in myelinating berg et al. (2018) propose a model where SCs undergo a switch from
SCs is required for myelin maintenance, as shown by tamoxifen- the myelin biogenesis state during developmental myelination to a
inducible SC-specific knockouts of these genes resulting in SC demye- homeostasis state in adults, where myelin genes are transcribed at
lination (Bremer et al., 2011; Decker et al., 2006). lower level as compared to the developmental active myelination
Once myelination ensues, myelinating SCs transition to a stage. In this study, the authors show that HDAC3 is an inducer of
homeostatic state where continuous expression of myelin genes is myelin gene expression (in contrast to the study of He et al., 2018),
required to a level necessary for maintenance of the myelin sheath. but that HDAC3 is necessary for the transition into the homeostasis
The regulation of Krox20 during myelin homeostasis is key to stage. Deletion of HDAC3 in SCs prevents this transition and instead
maintain the myelin structure and avoid demyelination or hyper- leads to the maintenance of myelin biogenesis by HDAC2. This even-
myelination. This regulation can be achieved by histone modifica- tually leads to hypermyelination followed by demyelination, and to
tions (Salzer, 2015). For instance, H3K9me3 repressive marks are the development of a severe peripheral neuropathy in adult mice
enriched at the Myelinating SC element (MSE) of the Krox20 gene (Rosenberg et al., 2018).
and at the SC specific enhancer (SCE) of the Oct6 gene in adult SCs Interestingly, a recent study reports on the functions of KDM8
(Brügger et al., 2017), maintaining lower levels of Krox20 and Oct6 (also known as JMJD5)—a rarely studied KDM in neuroscience—that
transcription as compared to developing SCs during the active mye- demethylates H3K36me2 and thereby decreases the activation of the
lination phase. demethylated locus. In this study, Fuhrmann, Mernberger, Nist,
Other repressive histone methylation marks such as H3K27me3 Stiewe, and Elsasser (2018) ablated the POZ (POxvirus and Zinc fin-
also contribute to the maintenance of the myelinating state: mature ger) domain of the transcription factor Miz1 (Myc-interacting zinc fin-
myelinating SCs exhibit H3K27me3 marks on promoters of injury- ger protein 1) in SCs, which led to the development of a peripheral
induced genes through histone methyltransferase activity of the neuropathy within 90 days. The authors identified KDM8 as a direct
DUMAN ET AL. 1589
target of Miz1, which represses KDM8 expression. Deletion of the 1996): it is required for timely expression of the promyelinating factor
POZ domain of Miz1 in SCs results in increased KDM8 levels and Krox20 but needs to be downregulated for myelination to proceed
decreased H3K36me2 marks at regulatory regions of cell cycle-related (Ryu et al., 2007). HDAC2 interacts directly with the transcription fac-
genes. This induces SC hyperproliferation and the development of a tor Sox10 and recruits the H3K9 demethylases JMJD2C and KDM3A
late-onset demyelinating neuropathy (Fuhrmann et al., 2018). to de-repress and activate the Oct6 promoter, which results in
increased expression of Oct6 and subsequently prevents early
upregulation of c-Jun after lesion (Brügger et al., 2017). Consistent
6 | FUNCTIONS OF HISTONE with this, the authors show that ablation of HDAC1/2 or of Oct6 pre-
MODIFICATIONS AND HISTONE MODIFIERS vents Oct6 re-expression after lesion and leads to earlier and higher
IN PERIPHERAL NERVE INJURY RESPONSE upregulation of c-Jun and to faster axonal regrowth. During the
remyelination phase of nerve injury response, HDAC2 and Sox10
The process of SC response to peripheral nerve injury involves inhibi- recruit again JMJD2C and KDM3A, but this time to the Myelinating
tion of myelination promoting genes and activation of regeneration SC element (MSE) of the Krox20 gene, de-repressing and activating
promoting factors (Jessen & Mirsky, 2016). In the early stages follow- the transcription of Krox20 and thus upregulating Krox20, which
ing peripheral nerve injury, the activation of injury-related genes is mediates remyelination. Ablation of HDAC2 and its homologous pro-
promoted by the removal of the repressive histone mark H3K27me3 tein HDAC1 prevents Krox20 upregulation and leads to impaired
and the gain of the active histone mark H3K4me3, at their promoter remyelination (Brügger et al., 2017). Interestingly, a short-term 3-day
regions. At the same time, ChIP-seq analysis using H3K27Ac-marked treatment after lesion with the HDAC1/2 inhibitor Mocetinostat does
regulatory elements identified approximately 4,000 injury-induced not impair remyelination but accelerates axonal regrowth and func-
enhancers. Enhancers of positive regulators of myelination like tional recovery (Brügger et al., 2017). In this case, HDAC1/2 do not
Krox20 and Sox10 exhibit loss of the active histone mark H3K27Ac, act as histone modifying enzymes but rather as protein mediators.
while enhancers of negative regulators of myelination like c-Jun, Shh, Studies have also revealed the role of HDAC3 in nerve injury
and GDNF gain H3K27Ac (Hung et al., 2015; Ma, Hung, & Svaren, response. He et al. (2018) report that in the early stages following
2016; Jessen & Mirsky, 2019b). injury, HDAC3 exerts an inhibitory effect through H3K27
The requirement of histone modifiers in nerve injury response deacetylation, which results in the silencing of genes encoding pro-
has recently been investigated. The acute phase of nerve injury teins with promyelinating functions, thus acting as a transcriptional
response is regulated by HDAC2, which coordinates the action of repressor (He et al., 2018). Pharmacological inhibition of HDAC3
other chromatin remodeling enzymes to induce the upregulation of showed enhanced myelin growth and regeneration and improved
Oct6, a key transcription factor for SC development (Brügger et al., functional recovery after peripheral nerve injury in mice (He et al.,
2017). Oct6 is an intermediate inducer of myelination (Jaegle et al., 2018). In this study, animals have been treated immediately after
F IGURE 1 Histone modifications and histone modifiers in Schwann cell (SC) development and maintenance. Schematic representation of
mechanisms related to histone modifications and histone modifiers in SCs during development and maintenance of peripheral nervous system
(PNS) integrity
1590 DUMAN ET AL.
lesion and for several days with the HDAC3 inhibitor, leading to pre- profiling analyses revealed that HDAC3 represses promyelinating
cocious remyelination. The relevance of such a treatment appears programs through epigenetic silencing while coordinating with
however unclear at this early time-point after lesion, since promoting p300 HAT to activate myelination-inhibitory programs that include
remyelination too early is very likely to interfere with the conversion the HIPPO signaling effector TEAD4 to inhibit myelin growth
of SCs into repair cells and thus with axonal regrowth (Arthur- (He et al., 2018).
Farraj et al., 2012). In this context, it would be interesting to mea- Recently, the role of non-coding RNAs in the regulation of gene
sure the levels of c-Jun early after lesion in SCs of mice treated transcription (Hawkins & Morris, 2008) has been described. First
with an HDAC3 inhibitor or where HDAC3 has been deleted. In observed in doubly transformed tobacco plants, small double-stranded
this study, HDAC3 was shown to antagonize the myelinogenic RNAs were shown to direct epigenetic changes such as DNA methyla-
neuregulin-PI3K-AKT signaling axis. Moreover, genome-wide tion to loci containing homology to the small RNA (Matzke, Primig,
F IGURE 2 Histone modifications and histone modifiers in Schwann cells (SCs) after lesion. Schematic representation of mechanisms related
to histone modifications and histone modifiers in SC response to injury and peripheral nervous system (PNS) regeneration
DUMAN ET AL. 1591
Trnovsky, & Matzke, 1989). The phenomenon was termed small RNA- study of Ma et al. (2018) showing increased expression of p19 and
directed transcriptional gene silencing (TGS). TGS was later shown in p16 in sciatic nerves of SC-specific Eed KO mice after sciatic nerve
Arabidopsis thaliana to require the action of RNA-dependent DNA crush injury. In this mouse mutant, the EED subunit of the PRC2 com-
methylation (Mette, Aufsatz, van der Winden, Matzke, & Matzke, plex is ablated, which prevents PRC2 complex-dependent H3K27
2000; Wassenegger, Heimes, Riedel, & Sanger, 1994) and members of methylation.
the Argonaute protein family (Lippman, May, Yordan, Singer, & The functions of histone modifications and histone modifiers in
Martienssen, 2003). TGS is mechanistically distinct from the abun- SCs during development, maintenance, and regeneration described
dantly studied post-transcriptional silencing pathway, which requires above are summarized in Figures 1 and 2.
Argonaute 2 (AGO2) and results in cleavage of the target mRNAs
(Morris, 2009a). Notably, TGS results in long-term stable epigenetic
modifications that can be passed on to daughter cells (Morris, 2009b). 7 | CONCLUSION
In human cells, there are two independent mechanisms that confer
TGS: (a) a miRNA-directed mechanism and (b) a long-antisense RNA During the past two decades, a growing number of studies have iden-
mechanism (Morris, 2009b). Both short (miRNA) and long (antisense) tified critical functions of histone modifications and histone modifiers
RNA-mediated TGS in human cells involve interaction of RNA with in SC biology. This area of research is very likely to expand a lot fur-
promoter regions (Kim, Saetrom, Snove Jr., & Rossi, 2008; Klase et al., ther, due to the various types of possible modifications that histones
2007; Omoto & Fujii, 2005; Tan et al., 2009). We and others can undergo. Indeed, recent progress in mass spectrometry methods
(Adilakshmi, Sudol, & Tapinos, 2012; Lin, Oksuz, Svaren, & and analyses has permitted to uncover novel histone modifications at
Awatramani, 2018; Viader, Chang, Fahrner, Nagarajan, & Milbrandt, a time-point where we are still far from fully understanding the func-
2011) have shown that a specific cohort of miRNAs controls directly tions of the previously known histone modifications. The good news
or indirectly the expression of positive and negative regulators of is that there is a lot more work for the next generation of scientists on
myelination and injury response such as Krox20, c-Jun, Sox2, Nanog, this topic, thus the scientific community working on the functions of
ID2, p75, QKI-6 through acute post-transcriptional gene silencing histone modifications and histone modifiers is likely to grow substan-
after PNS injury in vivo. Although miR-138 is dispensable for mye- tially together with our knowledge!
lination (Lin et al., 2018), miR-138 and miR-709 show the highest We already know that histone modifiers hold key functions in
affinity for binding and regulation of Krox20, c-Jun and Sox-2 regulating the activity and expression of transcription factors control-
expression (Adilakshmi et al., 2012), which are the main gene regula- ling SC development and SC functions in the maintenance of PNS
tors of demyelination and conversion into repair SCs following PNS integrity and its regeneration after lesion. The next step will be to put
injury (Jessen & Mirsky, 2008). We also demonstrated that miR-709 into practice what we have learnt. Indeed, many small-molecule inhibi-
is involved in regulating transcriptional gene silencing of Krox20 tors and activators of histone modifiers are already available and rep-
through direct interaction of miR-709 with the Krox20 MSE, which resent a tremendous potential for future treatment to restore
affects nascent transcription of Krox20, and through the formation myelination or promote axonal regeneration in the context of disease
of silencing complexes comprising the repressive histone mark or trauma. In addition, it is very likely that modulators of histone mod-
H3K27me3, AGO-1, and miR-709 recruited to the Krox20 promoter ifiers will lead to treatments for peripheral nerve sheath tumors, which
(Adilakshmi et al., 2012). Recently, Arthur-Farraj et al. (2017) identi- are mostly due to uncontrolled SC growth. Indeed, although not cov-
fied c-Jun and Foxd3 as potential regulators of certain miRNA in ered in this review, some peripheral nerve sheath tumors have been
repair SCs following nerve injury. After peripheral nerve injury, the correlated with changes in histone modifications in addition to DNA
expression of a long non-coding RNA antisense to the promoter of methylation. For instance, inactivation of the PRC2 complex and loss
Krox20 (Egr2-AS-RNA) is increased and correlates with decreased of the repressive methylation mark H3K27me3 were found in clusters
Krox20 transcript and protein levels. In vivo inhibition of Egr2-AS- of genes deregulated in cases of malignant peripheral nerve sheath
RNA following sciatic nerve injury reverts the Krox20-mediated tran- tumors (Lee et al., 2014; Rohrich et al., 2016). Another challenge
scriptional program and significantly delays demyelination. Egr2-AS- for the design of efficient treatments with low toxicity will be to
RNA gradually recruits H3K27Me3, AGO1, AGO2, and EZH2 on the increase the specificity of the available compounds. Indeed, the over-
Krox20 promoter following sciatic nerve injury to mediate inhibition view of the different studies on histone modifiers demonstrates spe-
of Krox20 transcription (Martinez-Moreno et al., 2017). cific functions for each enzyme. It is therefore of utmost importance
Following injury, SCs demyelinate, convert into repair cells and to be able to target specifically the enzyme involved in a given pro-
re-enter the cell cycle. Gomez-Sanchez et al. (2013) showed that the cess, first to understand their individual function and second to use
H3K27me3 demethylase JMJD3 (also known as KDM6B) is their function in human medicine.
upregulated in SCs after lesion and stimulates the activation of the
Ink4a/Arf locus by demethylating the promoter regions of p19Arf, ACKNOWLEDGMENTS
p16Ink4a and potentially also of p15Ink4b, which prevents uncon- Grant sponsors: International Foundation for Research in Paraplegia
trolled SC proliferation that could lead to tumor formation (Gomez- (IRP), grant number: P 174; Warren Alpert Foundation, NIH
Sanchez et al., 2013). These findings are further supported by the (1R21CA235415-01A1).
1592 DUMAN ET AL.
DATA AVAILABILITY STATEMENT critical for Schwann cell myelination. Nature Neuroscience, 14(4),
Data sharing is not applicable to this article as no new data were cre- 437–441. https://doi.org/10.1038/nn.2780
Chen, Z. L., Yu, W. M., & Strickland, S. (2007). Peripheral regeneration.
ated or analyzed in this study.
Annual Review of Neuroscience, 30, 209–233. https://doi.org/10.1146/
annurev.neuro.30.051606.094337
ORCID Chittka, A., Arevalo, J. C., Rodriguez-Guzman, M., Perez, P., Chao, M. V., &
Claire Jacob https://orcid.org/0000-0001-9567-3950 Sendtner, M. (2004). The p75NTR-interacting protein SC1 inhibits cell
cycle progression by transcriptional repression of cyclin E. The Journal
of Cell Biology, 164(7), 985–996. https://doi.org/10.1083/jcb.
REFERENCES 200301106
Adilakshmi, T., Sudol, I., & Tapinos, N. (2012). Combinatorial action of de Ruijter, A. J., van Gennip, A. H., Caron, H. N., Kemp, S., & van
miRNAs regulates transcriptional and post-transcriptional gene silenc- Kuilenburg, A. B. (2003). Histone deacetylases (HDACs): Characteriza-
ing following in vivo PNS injury. PLoS One, 7(7), e39674. https://doi. tion of the classical HDAC family. The Biochemical Journal, 370(Pt 3),
org/10.1371/journal.pone.0039674 737–749. https://doi.org/10.1042/BJ20021321
Andrews, F. H., Strahl, B. D., & Kutateladze, T. G. (2016). Insights into Decker, L., Desmarquet-Trin-Dinh, C., Taillebourg, E., Ghislain, J.,
newly discovered marks and readers of epigenetic information. Nature Vallat, J. M., & Charnay, P. (2006). Peripheral myelin maintenance
Chemical Biology, 12(9), 662–668. https://doi.org/10.1038/nchembio. is a dynamic process requiring constant Krox20 expression. The
2149 Journal of Neuroscience, 26(38), 9771–9779. https://doi.org/10.1523/
Arthur-Farraj, P. J., Latouche, M., Wilton, D. K., Quintes, S., Chabrol, E., JNEUROSCI.0716-06.2006
Banerjee, A., … Jessen, K. R. (2012). c-Jun reprograms Schwann cells Deckert, J., & Struhl, K. (2001). Histone acetylation at promoters is differ-
of injured nerves to generate a repair cell essential for regeneration. entially affected by specific activators and repressors. Molecular and
Neuron, 75(4), 633–647. https://doi.org/10.1016/j.neuron.2012. Cellular Biology, 21(8), 2726–2735. https://doi.org/10.1128/MCB.21.
06.021 8.2726-2735.2001
Arthur-Farraj, P. J., Morgan, C. C., Adamowicz, M., Gomez- Deng, Y., Wu, L. M. N., Bai, S., Zhao, C., Wang, H., Wang, J., … Lu, Q. R.
Sanchez, J. A., Fazal, S. V., Beucher, A., … Aitman, T. J. (2017). (2017). A reciprocal regulatory loop between TAZ/YAP and G-protein
Changes in the coding and non-coding transcriptome and DNA Gαs regulates Schwann cell proliferation and myelination. Nature Com-
methylome that define the Schwann cell repair phenotype after munications, 8, 15161. https://doi.org/10.1038/ncomms15161
nerve injury. Cell Reports, 20(11), 2719–2734. https://doi.org/10. Dieker, J., & Muller, S. (2010). Epigenetic histone code and autoimmunity.
1016/j.celrep.2017.08.064 Clinical Reviews in Allergy and Immunology, 39(1), 78–84. https://doi.
Auerbach, R. (1954). Analysis of the developmental effects of a lethal org/10.1007/s12016-009-8173-7
mutation in the house mouse. Journal of Experimental Zoology, 127(2), Ernst, J., Kheradpour, P., Mikkelsen, T. S., Shoresh, N., Ward, L. D.,
305–329. https://doi.org/10.1002/jez.1401270206 Epstein, C. B., … Bernstein, B. E. (2011). Mapping and analysis of chro-
Bermingham, J. R., Jr., Scherer, S. S., O'Connell, S., Arroyo, E., Kalla, K. A., matin state dynamics in nine human cell types. Nature, 473(7345),
Powell, F. L., & Rosenfeld, M. G. (1996). Tst-1/Oct-6/SCIP regulates a 43–49. https://doi.org/10.1038/nature09906
unique step in peripheral myelination and is required for normal respi- Fernando, R. N., Cotter, L., Perrin-Tricaud, C., Berthelot, J., Bartolami, S.,
ration. Genes & Development, 10(14), 1751–1762. https://doi.org/10. Pereira, J. A., … Tricaud, N. (2016). Optimal myelin elongation relies on
1101/gad.10.14.1751 YAP activation by axonal growth and inhibition by Crb3/Hippo path-
Bremer, M., Frob, F., Kichko, T., Reeh, P., Tamm, E. R., Suter, U., & way. Nature Communications, 7, 12186. https://doi.org/10.1038/
Wegner, M. (2011). Sox10 is required for Schwann-cell homeostasis ncomms12186
and myelin maintenance in the adult peripheral nerve. Glia, 59(7), Finzsch, M., Schreiner, S., Kichko, T., Reeh, P., Tamm, E. R., Bosl, M. R., …
1022–1032. https://doi.org/10.1002/glia.21173 Wegner, M. (2010). Sox10 is required for Schwann cell identity and
Britsch, S., Goerich, D. E., Riethmacher, D., Peirano, R. I., Rossner, M., progression beyond the immature Schwann cell stage. The Journal of
Nave, K. A., … Wegner, M. (2001). The transcription factor Sox10 is a Cell Biology, 189(4), 701–712. https://doi.org/10.1083/jcb.
key regulator of peripheral glial development. Genes & Development, 200912142
15(1), 66–78. https://doi.org/10.1101/gad.186601 Franz, T. (1990). Defective ensheathment of motoric nerves in the splotch
Brügger, V., Duman, M., Bochud, M., Munger, E., Heller, M., Ruff, S., & mutant mouse. Acta Anatomica (Basel), 138(3), 246–253. https://doi.
Jacob, C. (2017). Delaying histone deacetylase response to injury org/10.1159/000146947
accelerates conversion into repair Schwann cells and nerve regenera- Frob, F., Bremer, M., Finzsch, M., Kichko, T., Reeh, P., Tamm, E. R., …
tion. Nature Communications, 8, 14272. https://doi.org/10.1038/ Wegner, M. (2012). Establishment of myelinating Schwann cells and
ncomms14272 barrier integrity between central and peripheral nervous systems
Brügger, V., Engler, S., Pereira, J. A., Ruff, S., Horn, M., Welzl, H., … depend on Sox10. Glia, 60(5), 806–819. https://doi.org/10.1002/glia.
Jacob, C. (2015). HDAC1/2-dependent P0 expression maintains para- 22310
nodal and nodal integrity independently of myelin stability through Fuhrmann, D., Mernberger, M., Nist, A., Stiewe, T., & Elsasser, H. P. (2018).
interactions with neurofascins. PLoS Biology, 13(9), e1002258. https:// Miz1 controls Schwann cell proliferation via H3K36(me2) demethylase
doi.org/10.1371/journal.pbio.1002258 Kdm8 to prevent peripheral nerve demyelination. The Journal of Neuro-
Carrozza, M. J., Utley, R. T., Workman, J. L., & Côté, J. (2003). The diverse science, 38(4), 858–877. https://doi.org/10.1523/JNEUROSCI.0843-
functions of histone acetyltransferase complexes. Trends in Genetics, 17.2017
19(6), 321–329. https://doi.org/10.1016/s0168-9525(03)00115-x Ghislain, J., Desmarquet-Trin-Dinh, C., Jaegle, M., Meijer, D.,
Casadio, F., Lu, X., Pollock, S. B., LeRoy, G., Garcia, B. A., Muir, T. W., … Charnay, P., & Frain, M. (2002). Characterisation of cis-acting
Allis, C. D. (2013). H3R42me2a is a histone modification with positive sequences reveals a biphasic, axon-dependent regulation of
transcriptional effects. Proceedings of the National Academy of Sciences Krox20 during Schwann cell development. Development, 129(1),
of the United States of America, 110(37), 14894–14899. https://doi. 155–166. Retrieved from. https://www.ncbi.nlm.nih.gov/pubmed/
org/10.1073/pnas.1312925110 11782409
Chen, Y., Wang, H., Yoon, S. O., Xu, X., Hottiger, M. O., Svaren, J., … Gökbuget, D., Pereira, J. A., Bachofner, S., Marchais, A., Ciaudo, C.,
Lu, Q. R. (2011). HDAC-mediated deacetylation of NF-kappaB is Stoffel, M., … Suter, U. (2015). The Lin28/let-7 axis is critical for
DUMAN ET AL. 1593
myelination in the peripheral nervous system. Nature Communications, Jacob, C., Lotscher, P., Engler, S., Baggiolini, A., Varum Tavares, S.,
6, 8584. https://doi.org/10.1038/ncomms9584 Brugger, V., … Suter, U. (2014). HDAC1 and HDAC2 control the speci-
Gomez-Sanchez, J. A., Carty, L., Iruarrizaga-Lejarreta, M., Palomo- fication of neural crest cells into peripheral glia. The Journal of Neuro-
Irigoyen, M., Varela-Rey, M., Griffith, M., … Jessen, K. R. (2015). science, 34(17), 6112–6122. https://doi.org/10.1523/JNEUROSCI.
Schwann cell autophagy, myelinophagy, initiates myelin clearance 5212-13.2014
from injured nerves. The Journal of Cell Biology, 210(1), 153–168. Jacques-Fricke, B. T., & Gammill, L. S. (2014). Neural crest specification
https://doi.org/10.1083/jcb.201503019 and migration independently require NSD3-related lysine methyl-
Gomez-Sanchez, J. A., Gomis-Coloma, C., Morenilla-Palao, C., Peiro, G., transferase activity. Molecular Biology of the Cell, 25(25), 4174–4186.
Serra, E., Serrano, M., & Cabedo, H. (2013). Epigenetic induction of the https://doi.org/10.1091/mbc.E13-12-0744
Ink4a/Arf locus prevents Schwann cell overproliferation during nerve Jaegle, M., Mandemakers, W., Broos, L., Zwart, R., Karis, A., Visser, P., …
regeneration and after tumorigenic challenge. Brain, 136(Pt 7), Meijer, D. (1996). The POU factor Oct-6 and Schwann cell differentia-
2262–2278. https://doi.org/10.1093/brain/awt130 tion. Science, 273(5274), 507–510. https://doi.org/10.1126/science.
Gomis-Coloma, C., Velasco-Aviles, S., Gomez-Sanchez, J. A., Casillas- 273.5274.507
Bajo, A., Backs, J., & Cabedo, H. (2018). Class IIa histone deacetylases Jenuwein, T., & Allis, C. D. (2001). Translating the histone code. Science,
link cAMP signaling to the myelin transcriptional program of Schwann 293(5532), 1074–1080. https://doi.org/10.1126/science.1063127
cells. The Journal of Cell Biology, 217(4), 1249–1268. https://doi.org/ Jessen, K. R., & Arthur-Farraj, P. (2019). Repair Schwann cell update: Adap-
10.1083/jcb.201611150 tive reprogramming, EMT, and stemness in regenerating nerves. Glia,
Gordon, T., Chan, K. M., Sulaiman, O. A., Udina, E., Amirjani, N., & 67(3), 421–437. https://doi.org/10.1002/glia.23532
Brushart, T. M. (2009). Accelerating axon growth to overcome Jessen, K. R., & Mirsky, R. (2005). The origin and development of glial cells
limitations in functional recovery after peripheral nerve injury. Neuro- in peripheral nerves. Nature Reviews. Neuroscience, 6(9), 671–682.
surgery, 65(4 Suppl), A132–A144. https://doi.org/10.1227/01.NEU. https://doi.org/10.1038/nrn1746
0000335650.09473.D3 Jessen, K. R., & Mirsky, R. (2008). Negative regulation of myelination: Rele-
Greer, C. B., Tanaka, Y., Kim, Y. J., Xie, P., Zhang, M. Q., Park, I. H., & vance for development, injury, and demyelinating disease. Glia, 56(14),
Kim, T. H. (2015). Histone deacetylases positively regulate transcrip- 1552–1565. https://doi.org/10.1002/glia.20761
tion through the elongation machinery. Cell Reports, 13(7), Jessen, K. R., & Mirsky, R. (2016). The repair Schwann cell and its function
1444–1455. https://doi.org/10.1016/j.celrep.2015.10.013 in regenerating nerves. The Journal of Physiology, 594(13), 3521–3531.
Grove, M., Kim, H., Santerre, M., Krupka, A. J., Han, S. B., Zhai, J., … https://doi.org/10.1113/JP270874
Son, Y. J. (2017). YAP/TAZ initiate and maintain Schwann cell mye- Jessen, K. R., & Mirsky, R. (2019a). Schwann cell precursors; multipotent
lination. Elife, 6, e20982. https://doi.org/10.7554/eLife.20982 glial cells in embryonic nerves. Frontiers in Molecular Neuroscience, 12,
Hawkins, P. G., & Morris, K. V. (2008). RNA and transcriptional modulation 69. https://doi.org/10.3389/fnmol.2019.00069
of gene expression. Cell Cycle, 7(5), 602–607. Retrieved from. http:// Jessen, K. R., & Mirsky, R. (2019b). The success and failure of the Schwann
www.ncbi.nlm.nih.gov/pubmed/18256543 cell response to nerve injury. Frontiers in Cellular Neuroscience, 13, 33.
He, X., Zhang, L., Queme, L. F., Liu, X., Lu, A., Waclaw, R. R., … Lu, Q. R. https://doi.org/10.3389/fncel.2019.00033
(2018). A histone deacetylase 3-dependent pathway delimits periph- Jessen, K. R., Mirsky, R., & Lloyd, A. C. (2015). Schwann cells: Develop-
eral myelin growth and functional regeneration. Nature Medicine, 24 ment and role in nerve repair. Cold Spring Harbor Perspectives in Biol-
(3), 338–351. https://doi.org/10.1038/nm.4483 ogy, 7(7), a020487. https://doi.org/10.1101/cshperspect.a020487
Heinen, A., Tzekova, N., Graffmann, N., Torres, K. J., Uhrberg, M., Jopling, C., Boue, S., & Izpisua Belmonte, J. C. (2011). Dedifferentiation,
Hartung, H. P., & Kury, P. (2012). Histone methyltransferase enhancer transdifferentiation and reprogramming: Three routes to regeneration.
of zeste homolog 2 regulates Schwann cell differentiation. Glia, 60(11), Nature Reviews. Molecular Cell Biology, 12(2), 79–89. https://doi.org/
1696–1708. https://doi.org/10.1002/glia.22388 10.1038/nrm3043
Hodawadekar, S. C., & Marmorstein, R. (2007). Chemistry of acetyl trans- Kastriti, M. E., Kameneva, P., Kamenev, D., Dyachuk, V., Furlan, A.,
fer by histone modifying enzymes: Structure, mechanism and implica- Hampl, M., … Adameyko, I. (2019). Schwann cell precursors generate
tions for effector design. Oncogene, 26(37), 5528–5540. https://doi. the majority of chromaffin cells in Zuckerkandl organ and some sym-
org/10.1038/sj.onc.1210619 pathetic neurons in Paraganglia. Frontiers in Molecular Neuroscience,
Hung, H. A., Sun, G., Keles, S., & Svaren, J. (2015). Dynamic regulation of 12, 6. https://doi.org/10.3389/fnmol.2019.00006
Schwann cell enhancers after peripheral nerve injury. The Journal of Kim, D. H., Saetrom, P., Snove, O., Jr., & Rossi, J. J. (2008). MicroRNA-
Biological Chemistry, 290(11), 6937–6950. https://doi.org/10.1074/ directed transcriptional gene silencing in mammalian cells. Proceedings
jbc.M114.622878 of the National Academy of Sciences of the United States of America,
Isaacman-Beck, J., Schneider, V., Franzini-Armstrong, C., & Granato, M. 105(42), 16230–16235. https://doi.org/10.1073/pnas.0808830105
(2015). The lh3 glycosyltransferase directs target-selective peripheral Klase, Z., Kale, P., Winograd, R., Gupta, M. V., Heydarian, M., Berro, R., …
nerve regeneration. Neuron, 88(4), 691–703. https://doi.org/10.1016/ Kashanchi, F. (2007). HIV-1 TAR element is processed by Dicer to yield
j.neuron.2015.10.004 a viral micro-RNA involved in chromatin remodeling of the viral LTR.
Jacob, C. (2015). Transcriptional control of neural crest specification into BMC Molecular Biology, 8, 63. https://doi.org/10.1186/1471-2199-8-63
peripheral glia. Glia, 63(11), 1883–1896. https://doi.org/10.1002/glia. Kuhlbrodt, K., Herbarth, B., Sock, E., Hermans-Borgmeyer, I., &
22816 Wegner, M. (1998). Sox10, a novel transcriptional modulator in glial
Jacob, C. (2017). Chromatin-remodeling enzymes in control of Schwann cells. The Journal of Neuroscience, 18(1), 237–250. Retrieved from.
cell development, maintenance and plasticity. Current Opinion in Neu- https://www.ncbi.nlm.nih.gov/pubmed/9412504
robiology, 47, 24–30. https://doi.org/10.1016/j.conb.2017.08.007 Lange, U. C., Siebert, S., Wossidlo, M., Weiss, T., Ziegler-Birling, C.,
Jacob, C., Christen, C. N., Pereira, J. A., Somandin, C., Baggiolini, A., Walter, J., … Schneider, R. (2013). Dissecting the role of H3K64me3 in
Lotscher, P., … Suter, U. (2011). HDAC1 and HDAC2 control the tran- mouse pericentromeric heterochromatin. Nature Communications, 4,
scriptional program of myelination and the survival of Schwann cells. 2233. https://doi.org/10.1038/ncomms3233
Nature Neuroscience, 14(4), 429–436. https://doi.org/10.1038/nn.2762 Lee, W., Teckie, S., Wiesner, T., Ran, L., Prieto Granada, C. N., Lin, M., …
Jacob, C., Lebrun-Julien, F., & Suter, U. (2011). How histone deacetylases Chi, P. (2014). PRC2 is recurrently inactivated through EED or SUZ12
control myelination. Molecular Neurobiology, 44(3), 303–312. https:// loss in malignant peripheral nerve sheath tumors. Nature Genetics, 46
doi.org/10.1007/s12035-011-8198-9 (11), 1227–1232. https://doi.org/10.1038/ng.3095
1594 DUMAN ET AL.
Lin, H. P., Oksuz, I., Svaren, J., & Awatramani, R. (2018). Egr2-dependent Structural & Molecular Biology, 19(12), 1218–1227. https://doi.org/10.
microRNA-138 is dispensable for peripheral nerve myelination. 1038/nsmb.2436
Scientific Reports, 8(1), 3817. https://doi.org/10.1038/s41598-018- Nave, K. A., & Schwab, M. H. (2005). Glial cells under remote control.
22010-8 Nature Neuroscience, 8(11), 1420–1422. https://doi.org/10.1038/
Lippman, Z., May, B., Yordan, C., Singer, T., & Martienssen, R. (2003). Dis- nn1105-1420
tinct mechanisms determine transposon inheritance and methylation Nave, K. A., & Trapp, B. D. (2008). Axon-glial signaling and the glial support
via small interfering RNA and histone modification. PLoS Biology, 1(3), of axon function. Annual Review of Neuroscience, 31, 535–561. https://
E67. https://doi.org/10.1371/journal.pbio.0000067 doi.org/10.1146/annurev.neuro.30.051606.094309
Liu, A., Li, J., Marin-Husstege, M., Kageyama, R., Fan, Y., Gelinas, C., & Nave, K. A., & Werner, H. B. (2014). Myelination of the nervous system:
Casaccia-Bonnefil, P. (2006). A molecular insight of Hes5-dependent Mechanisms and functions. Annual Review of Cell and Developmental
inhibition of myelin gene expression: Old partners and new players. Biology, 30, 503–533. https://doi.org/10.1146/annurev-cellbio-
The EMBO Journal, 25(20), 4833–4842. https://doi.org/10.1038/sj. 100913-013101
emboj.7601352 Ness, J. K., Skiles, A. A., Yap, E. H., Fajardo, E. J., Fiser, A., & Tapinos, N.
Lopez-Anido, C., Poitelon, Y., Gopinath, C., Moran, J. J., Ma, K. H., (2016). Nuc-ErbB3 regulates H3K27me3 levels and HMT activity to
Law, W. D., … Svaren, J. (2016). Tead1 regulates the expression of establish epigenetic repression during peripheral myelination. Glia, 64
peripheral myelin protein 22 during Schwann cell development. (6), 977–992. https://doi.org/10.1002/glia.22977
Human Molecular Genetics, 25(14), 3055–3069. https://doi.org/10. Nocetti, N., & Whitehouse, I. (2016). Nucleosome repositioning underlies
1093/hmg/ddw158 dynamic gene expression. Genes & Development, 30(6), 660–672.
Ma, K. H., Duong, P., Moran, J. J., Junaidi, N., & Svaren, J. (2018). Pol- https://doi.org/10.1101/gad.274910.115
ycomb repression regulates Schwann cell proliferation and axon Olaopa, M., Zhou, H. M., Snider, P., Wang, J., Schwartz, R. J.,
regeneration after nerve injury. Glia, 66(11), 2487–2502. https://doi. Moon, A. M., & Conway, S. J. (2011). Pax3 is essential for normal car-
org/10.1002/glia.23500 diac neural crest morphogenesis but is not required during migration
Ma, K. H., Hung, H. A., Srinivasan, R., Xie, H., Orkin, S. H., & Svaren, J. nor outflow tract septation. Developmental Biology, 356(2), 308–322.
(2015). Regulation of peripheral nerve myelin maintenance by gene https://doi.org/10.1016/j.ydbio.2011.05.583
repression through polycomb repressive complex 2. The Journal of Omoto, S., & Fujii, Y. R. (2005). Regulation of human immunodeficiency
Neuroscience, 35(22), 8640–8652. https://doi.org/10.1523/ virus 1 transcription by nef microRNA. The Journal of General Virology,
JNEUROSCI.2257-14.2015 86(Pt 3), 751–755. https://doi.org/10.1099/vir.0.80449-0
Ma, K. H., Hung, H. A., & Svaren, J. (2016). Epigenomic regulation Paratore, C., Goerich, D. E., Suter, U., Wegner, M., & Sommer, L. (2001).
of Schwann cell reprogramming in peripheral nerve injury. The Survival and glial fate acquisition of neural crest cells are regulated by
Journal of Neuroscience, 36(35), 9135–9147. https://doi.org/10.1523/ an interplay between the transcription factor Sox10 and extrinsic com-
JNEUROSCI.1370-16.2016 binatorial signaling. Development, 128(20), 3949–3961. Retrieved
Maro, G. S., Vermeren, M., Voiculescu, O., Melton, L., Cohen, J., from. https://www.ncbi.nlm.nih.gov/pubmed/11641219
Charnay, P., & Topilko, P. (2004). Neural crest boundary cap cells con- Parkinson, D. B., Bhaskaran, A., Arthur-Farraj, P., Noon, L. A.,
stitute a source of neuronal and glial cells of the PNS. Nature Neurosci- Woodhoo, A., Lloyd, A. C., … Jessen, K. R. (2008). c-Jun is a negative
ence, 7(9), 930–938. https://doi.org/10.1038/nn1299 regulator of myelination. The Journal of Cell Biology, 181(4), 625–637.
Martinez-Moreno, M., O'Shea, T. M., Zepecki, J. P., Olaru, A., Ness, J. K., https://doi.org/10.1083/jcb.200803013
Langer, R., & Tapinos, N. (2017). Regulation of peripheral myelination Parrinello, S., Napoli, I., Ribeiro, S., Wingfield Digby, P., Fedorova, M.,
through transcriptional buffering of Egr2 by an antisense long non- Parkinson, D. B., … Lloyd, A. C. (2010). EphB signaling directs periph-
coding RNA. Cell Reports, 20(8), 1950–1963. https://doi.org/10.1016/ eral nerve regeneration through Sox2-dependent Schwann cell sorting.
j.celrep.2017.07.068 Cell, 143(1), 145–155. https://doi.org/10.1016/j.cell.2010.08.039
Matzke, M. A., Primig, M., Trnovsky, J., & Matzke, A. J. (1989). Reversible Pattaroni, C., & Jacob, C. (2013). Histone methylation in the nervous sys-
methylation and inactivation of marker genes in sequentially trans- tem: Functions and dysfunctions. Molecular Neurobiology, 47(2),
formed tobacco plants. The EMBO Journal, 8(3), 643–649. Retrieved 740–756. https://doi.org/10.1007/s12035-012-8376-4
from. http://www.ncbi.nlm.nih.gov/pubmed/16453872 Pereira, J. A., Lebrun-Julien, F., & Suter, U. (2012). Molecular mechanisms
Mette, M. F., Aufsatz, W., van der Winden, J., Matzke, M. A., & regulating myelination in the peripheral nervous system. Trends in Neu-
Matzke, A. J. (2000). Transcriptional silencing and promoter methyla- rosciences, 35(2), 123–134. https://doi.org/10.1016/j.tins.2011.
tion triggered by double-stranded RNA. The EMBO Journal, 19(19), 11.006
5194–5201. https://doi.org/10.1093/emboj/19.19.5194 Poitelon, Y., Lopez-Anido, C., Catignas, K., Berti, C., Palmisano, M.,
Michan, S., & Sinclair, D. (2007). Sirtuins in mammals: Insights into their Williamson, C., … Feltri, M. L. (2016). YAP and TAZ control peripheral
biological function. The Biochemical Journal, 404(1), 1–13. https://doi. myelination and the expression of laminin receptors in Schwann cells.
org/10.1042/BJ20070140 Nature Neuroscience, 19(7), 879–887. https://doi.org/10.1038/nn.
Morris, K. V. (2009a). Long antisense non-coding RNAs function to direct 4316
epigenetic complexes that regulate transcription in human cells. Epige- Rahman, S., Sowa, M. E., Ottinger, M., Smith, J. A., Shi, Y., Harper, J. W., &
netics, 4(5), 296–301. Retrieved from. http://www.ncbi.nlm.nih.gov/ Howley, P. M. (2011). The Brd4 extraterminal domain confers tran-
pubmed/19633414 scription activation independent of pTEFb by recruiting multiple pro-
Morris, K. V. (2009b). RNA-directed transcriptional gene silencing and acti- teins, including NSD3. Molecular and Cellular Biology, 31(13),
vation in human cells. Oligonucleotides, 19(4), 299–306. https://doi. 2641–2652. https://doi.org/10.1128/MCB.01341-10
org/10.1089/oli.2009.0212 Roberts, S. L., Dun, X. P., Doddrell, R. D. S., Mindos, T., Drake, L. K.,
Morton, P. D., Dellarole, A., Theus, M. H., Walters, W. M., Berge, S. S., & Onaitis, M. W., … Parkinson, D. B. (2017). Sox2 expression in Schwann
Bethea, J. R. (2013). Activation of NF-kappaB in Schwann cells is dis- cells inhibits myelination in vivo and induces influx of macrophages to
pensable for myelination in vivo. The Journal of Neuroscience, 33(24), the nerve. Development, 144(17), 3114–3125. https://doi.org/10.
9932–9936. https://doi.org/10.1523/JNEUROSCI.2483-12.2013 1242/dev.150656
Musselman, C. A., Lalonde, M. E., Côté, J., & Kutateladze, T. G. (2012). Per- Rohrich, M., Koelsche, C., Schrimpf, D., Capper, D., Sahm, F., Kratz, A., …
ceiving the epigenetic landscape through histone readers. Nature Reuss, D. E. (2016). Methylation-based classification of benign and
DUMAN ET AL. 1595
malignant peripheral nerve sheath tumors. Acta Neuropathologica, 131 Vargas, M. E., & Barres, B. A. (2007). Why is Wallerian degeneration in the
(6), 877–887. https://doi.org/10.1007/s00401-016-1540-6 CNS so slow? Annual Review of Neuroscience, 30, 153–179. https://
Rosenberg, L. H., Cattin, A. L., Fontana, X., Harford-Wright, E., doi.org/10.1146/annurev.neuro.30.051606.094354
Burden, J. J., White, I. J., … Lloyd, A. C. (2018). HDAC3 regulates the Veneti, Z., Gkouskou, K. K., & Eliopoulos, A. G. (2017). Polycomb repres-
transition to the homeostatic myelinating Schwann cell state. Cell sor complex 2 in genomic instability and cancer. International Journal
Reports, 25(10), 2755–2765 e2755. https://doi.org/10.1016/j.celrep. of Molecular Sciences, 18(8), E1657. https://doi.org/10.3390/
2018.11.045 ijms18081657
Ryu, E. J., Wang, J. Y., Le, N., Baloh, R. H., Gustin, J. A., Schmidt, R. E., & Viader, A., Chang, L. W., Fahrner, T., Nagarajan, R., & Milbrandt, J. (2011).
Milbrandt, J. (2007). Misexpression of Pou3f1 results in peripheral MicroRNAs modulate Schwann cell response to nerve injury by rein-
nerve hypomyelination and axonal loss. The Journal of Neuroscience, 27 forcing transcriptional silencing of dedifferentiation-related genes. The
(43), 11552–11559. https://doi.org/10.1523/JNEUROSCI.5497-06. Journal of Neuroscience: The Official Journal of the Society for Neurosci-
2007 ence, 31(48), 17358–17369. https://doi.org/10.1523/JNEUROSCI.
Salzer, J. L. (2015). Schwann cell myelination. Cold Spring Harbor Perspec- 3931-11.2011
tives in Biology, 7(8), a020529. https://doi.org/10.1101/cshperspect. Walport, L. J., Hopkinson, R. J., Chowdhury, R., Schiller, R., Ge, W.,
a020529 Kawamura, A., & Schofield, C. J. (2016). Arginine demethylation is
Schwarz, D., Varum, S., Zemke, M., Schöler, A., Baggiolini, A., catalysed by a subset of JmjC histone lysine demethylases. Nature
Draganova, K., … Sommer, L. (2014). Ezh2 is required for neural crest- Communications, 7, 11974. https://doi.org/10.1038/ncomms11974
derived cartilage and bone formation. Development, 141(4), 867–877. Wang, Z., Zang, C., Cui, K., Schones, D. E., Barski, A., Peng, W., & Zhao, K.
https://doi.org/10.1242/dev.094342 (2009). Genome-wide mapping of HATs and HDACs reveals distinct
Schwenty-Lara, J., Nehl, D., & Borchers, A. (2019). The histone methyl- functions in active and inactive genes. Cell, 138(5), 1019–1031.
transferase KMT2D, mutated in Kabuki syndrome patients, is required https://doi.org/10.1016/j.cell.2009.06.049
for neural crest cell formation and migration. Human Molecular Genet- Wassenegger, M., Heimes, S., Riedel, L., & Sanger, H. L. (1994). RNA-
ics. https://doi.org/10.1093/hmg/ddz284 [Epub ahead of print]. directed de novo methylation of genomic sequences in plants. Cell, 76
Sock, E., & Wegner, M. (2019). Transcriptional control of myelination and (3), 567–576. Retrieved from. http://www.ncbi.nlm.nih.gov/pubmed/
remyelination. Glia, 67(11), 2153–2165. https://doi.org/10.1002/glia. 8313476
23636 Weider, M., & Wegner, M. (2017). SoxE factors: Transcriptional regulators
Stassart, R. M., Fledrich, R., Velanac, V., Brinkmann, B. G., Schwab, M. H., of neural differentiation and nervous system development. Seminars in
Meijer, D., … Nave, K. A. (2013). A role for Schwann cell-derived Cell & Developmental Biology, 63, 35–42. https://doi.org/10.1016/j.
neuregulin-1 in remyelination. Nature Neuroscience, 16(1), 48–54. semcdb.2016.08.013
https://doi.org/10.1038/nn.3281 Woodhoo, A., Alonso, M. B., Droggiti, A., Turmaine, M., D'Antonio, M.,
Stierli, S., Imperatore, V., & Lloyd, A. C. (2019). Schwann cell plasticity- Parkinson, D. B., … Jessen, K. R. (2009). Notch controls embryonic
roles in tissue homeostasis, regeneration, and disease. Glia, 67(11), Schwann cell differentiation, postnatal myelination and adult plasticity.
2203–2215. https://doi.org/10.1002/glia.23643 Nature Neuroscience, 12(7), 839–847. https://doi.org/10.1038/nn.
Strahl, B. D., & Allis, C. D. (2000). The language of covalent histone modifi- 2323
cations. Nature, 403(6765), 41–45. https://doi.org/10.1038/47412 Woodhoo, A., & Sommer, L. (2008). Development of the Schwann cell line-
Strobl-Mazzulla, P. H., Sauka-Spengler, T., & Bronner-Fraser, M. (2010). age: From the neural crest to the myelinated nerve. Glia, 56(14),
Histone demethylase JmjD2A regulates neural crest specification. 1481–1490. https://doi.org/10.1002/glia.20723
Developmental Cell, 19(3), 460–468. https://doi.org/10.1016/j.devcel. Wu, L. M., Wang, J., Conidi, A., Zhao, C., Wang, H., Ford, Z., … Lu, Q. R.
2010.08.009 (2016). Zeb2 recruits HDAC-NuRD to inhibit notch and controls
Svaren, J., & Meijer, D. (2008). The molecular machinery of myelin gene Schwann cell differentiation and remyelination. Nature Neuroscience,
transcription in Schwann cells. Glia, 56(14), 1541–1551. https://doi. 19(8), 1060–1072. https://doi.org/10.1038/nn.4322
org/10.1002/glia.20767 Zhang, J., Jing, L., Li, M., He, L., & Guo, Z. (2019). Regulation of histone
Tan, Y., Zhang, B., Wu, T., Skogerbo, G., Zhu, X., Guo, X., … Chen, R. arginine methylation/demethylation by methylase and demethylase
(2009). Transcriptional inhibiton of Hoxd4 expression by miRNA-10a (review). Molecular Medicine Reports, 19(5), 3963–3971. https://doi.
in human breast cancer cells. BMC Molecular Biology, 10, 12. https:// org/10.3892/mmr.2019.10111
doi.org/10.1186/1471-2199-10-12 Zhao, S., Yue, Y., Li, Y., & Li, H. (2019). Identification and characterization
Topilko, P., Schneider-Maunoury, S., Levi, G., Baron-Van Evercooren, A., of ‘readers’ for novel histone modifications. Current Opinion in Chemi-
Chennoufi, A. B., Seitanidou, T., … Charnay, P. (1994). Krox-20 con- cal Biology, 51, 57–65. https://doi.org/10.1016/j.cbpa.2019.04.001
trols myelination in the peripheral nervous system. Nature, 371(6500),
796–799. https://doi.org/10.1038/371796a0
Torchia, J., Glass, C., & Rosenfeld, M. G. (1998). Co-activators and co-
repressors in the integration of transcriptional responses. Current How to cite this article: Duman M, Martinez-Moreno M,
Opinion in Cell Biology, 10(3), 373–383. https://doi.org/10.1016/
Jacob C, Tapinos N. Functions of histone modifications and
s0955-0674(98)80014-8
Tsai, E., & Casaccia, P. (2019). Mechano-modulation of nuclear events reg- histone modifiers in Schwann cells. Glia. 2020;68:1584–1595.
ulating oligodendrocyte progenitor gene expression. Glia, 67(7), https://doi.org/10.1002/glia.23795
1229–1239. https://doi.org/10.1002/glia.23595