Authors:	Woronzow, Valentina
Title:	Generation of genetic and epigenetic variation during cellular senescence and early tumorigenesis in a human and nonhuman primate lung fibroblast model
Online publication date:	4-Apr-2024
Year of first publication:	2024
Language:	english
Abstract:	Cellular senescence has garnered greater attention as a fundamental contributor to chronic illness and functional decline in aging. Once they exceed a finite number of cell divisions, senescent cells undergo permanent growth arrest while still being metabolically active. By accumulation they pose significant challenges to the organism. The present work provides two approaches to investigate senescence in a human lung fibroblast model both genetically and epigenetically while incorporating induced tetraploidy as an early tumorigenesis model. First, I compared small non-coding RNA and transcriptomic changes in proliferating, senescent, and tetraploid IMR-90 cells by conducting sncRNA sequencing, transcriptomic NGS and a subsequent bioinformatical analysis. Overall, both senescent and tetraploid IMR-90 cells exhibit amplified miRNA profiles that are pertinent to cancer progression and inflammation, as demonstrated through miRNA ontology analysis. This provides a unique opportunity to investigate the relationship between cell proliferation arrest, excessive cell proliferation, and aberrant replication. Of particular interest is hsa-miR-29a-3p, which displays significant upregulation in senescent IMR-90 cells, suggesting its yet to be described potential as a reliable senescence marker in human fibroblasts. The hypothesis that decreasing miR-29a-3p levels may increase longevity has some merit. However, inhibiting miR-29a-3p in proliferating cells led to the accumulation of stress responses and the appearance of senescence-related patterns, as evidenced by the observed biomarkers. Consequently, the inhibition had adverse outcomes, indicating an association with the antagonistic pleiotropy model of aging. Epigenetic alterations, including loss of repressive constitutive heterochromatin, may result in LINE-1 derepression, a phenomenon often connected with senescence. In addition to epigenetic changes, structural variations in aging genomes can be caused by de novo retrotranspositions of transposable elements like SVAs, as well as de novo insertions of accumulated mitochondrial DNA into nuclear DNA. A kinetic enrichment approach was utilized to detect the nuclear flanks of de novo SVA insertions in senescent genomes. The technique was coupled with deep sequencing. Furthermore, the genomes of proliferating and senescent IMR-90 cells were compared through deep sequencing or by enriching nuclear DNA with AluScan technology. Evidence was uncovered for de novo SVA and numts integrations in senescent IMR-90 cells using both methods. I hypothesize that the structural disparities have an impact on the mechanisms associated with cellular senescence in human lung fibroblasts.
DDC:	500 Naturwissenschaften 500 Natural sciences and mathematics
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 10 Biologie
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-10230
URN:	urn:nbn:de:hebis:77-openscience-11309d76-cd87-440f-875b-cff2dbd40d1b3
Version:	Original work
Publication type:	Dissertation
License:	CC BY-ND
Information on rights of use:	https://creativecommons.org/licenses/by-nd/4.0/
Extent:	121 Seiten ; Illustrationen, Diagramme
Appears in collections:	JGU-Publikationen