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Abstract
The Polycomb repressive complexes PRC1 and PRC2 act non-redundantly at target genes to maintain transcriptional programs and ensure cellular identity. PRC2 methylates lysine 27 on histone H3 (H3K27me), while PRC1 mono-ubiquitinates histone H2A at lysine 119 (H2Aub1). Here we present engineered mouse embryonic stem cells (ESCs) targeting the PRC2 subunits EZH1 and EZH2 to discriminate between contributions of distinct H3K27 methylation states and the presence of PRC2/1 at chromatin. We generate catalytically inactive EZH2 mutant ESCs, demonstrating that H3K27 methylation, but not recruitment to the chromatin, is essential for proper ESC differentiation. We further show that EZH1 activity is sufficient to maintain repression of Polycomb targets by depositing H3K27me2/3 and preserving PRC1 recruitment. This occurs in the presence of altered H3K27me1 deposition at actively transcribed genes and by a diffused hyperacetylation of chromatin that compromises ESC developmental potential. Overall, this work provides insights for the contribution of diffuse chromatin invasion by acetyltransferases in PRC2-dependent loss of developmental control.
Highlights
The Polycomb repressive complexes PRC1 and PRC2 act non-redundantly at target genes to maintain transcriptional programs and ensure cellular identity
We further show that the activity of EZH1 is sufficient to deposit H3K27me[3] at all PRC2 target sites but is unable to spread this modification to neighboring chromatin
In order to dissect the role of H3K27 methylation from the assembly and recruitment of the PRC2 complex to chromatin, we generated a set of isogenic embryonic stem cells (ESCs) lines carrying different mutations by using CRISPR/Cas[9] engineering to target the PRC2 complex
Summary
The Polycomb repressive complexes PRC1 and PRC2 act non-redundantly at target genes to maintain transcriptional programs and ensure cellular identity. Polycomb group (PcG) proteins act as epigenetic regulators that ensure the maintenance of cell-specific transcriptional programs by exerting a crucial role during establishment of cellular identity and cell fate transitions This is guaranteed by the activity of two major PcG repressive complexes (PRCs), PRC1 and PRC2, that act non-redundantly at the same target genes to ensure proper gene repression via post-translational modifications of histone proteins[1]. PRCs maintain a critical role in adult life, with both PRC1 and PRC2 activities playing specific roles in controlling cell identity and tissue homeostasis[1] These same activities are frequently deregulated in different type of human tumors by genetic lesions that preferentially target PRC2 activity[1]. EZH1 and PRC2-EZH2 complexes are associated to a set of ancillary proteins that are not required for intrinsic PRC2 enzymatic activity but play distinct roles in regulating chromatin recruitment and activity[21,22,23,24,25,26]
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