Dual role of Med12 in PRC1-dependent gene repression & ncRNA-mediated transcriptional activation
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Abstract
Embryonic stem cells (ESCs) are cells derived from the inner cell mass of the blastocyst of the early-stage preimplantation embryo and constitute a unique cell population due to their capacity of self-renewal and differentiation. While self-renewal ensures the propagation of the stem cell population, with differentiation ESCs give rise to all three primary germ layers from which the tissues and organs of the developing embryo will be shaped. During this process, ESCs undergo stable changes in their epigenome that enables them to acquire new identities. Both in pluripotency and differentiation, ESCs are under a tight transcriptional program on the level of chromatin which controls the proper spatiotemporal gene expression. This epigenetic control requires the combinatorial action of gene-specific transcription factors (TFs), the general transcriptional machinery, ncRNAs and regulatory elements.
In an attempt to understand how genes which code for lineage-specification programs get activated in early differentiation, we studied the epigenetic changes which they acquire from pluripotency to early differentiation. We focused on genes which are silenced in pluripotency by Polycomb group complexes (PcGs) and more specifically by the PRC1 complex. This complex via Ring1b which is an E3 ligase, decorates the histone H2A with an ubiquitin mark, H2AK119ub, a histone modification considered to be a hallmark of gene repression. PRC1-repressed genes get activated in early differentiation via the displacement of Ring1b by the H2AK119ub-interacting protein, Zrf1. In this study we explored how PRC1 establishes the silencing of key developmental genes in pluripotency. We provide evidence of the interplay between Ring1b and the subunit Med12 of the Mediator co-activator complex, which restricts the expression of those genes in mouse ESCs. A set of these genes, get activated in early differentiation by Med12 in complex with ncRNAs. This step requires the assembly of Med12 with an additional Mediator subunit, Cdk8, a remodeling event which relies on the recruitment of the latter by Zrf1.
These findings contribute to a better understanding of how silencing by PRC1 is established in pluripotency and how this step sets the ground for the transition to early stem cell differentiation.