Abstract
Two distinct Polycomb complexes, PRC1 and PRC2, collaborate to maintain epigenetic repression of key developmental loci in embryonic stem cells (ESCs). PRC1 and PRC2 have histone modifying activities, catalyzing mono-ubiquitination of histone H2A (H2AK119u1) and trimethylation of H3 lysine 27 (H3K27me3), respectively. Compared to H3K27me3, localization and the role of H2AK119u1 are not fully understood in ESCs. Here we present genome-wide H2AK119u1 maps in ESCs and identify a group of genes at which H2AK119u1 is deposited in a Ring1-dependent manner. These genes are a distinctive subset of genes with H3K27me3 enrichment and are the central targets of Polycomb silencing that are required to maintain ESC identity. We further show that the H2A ubiquitination activity of PRC1 is dispensable for its target binding and its activity to compact chromatin at Hox loci, but is indispensable for efficient repression of target genes and thereby ESC maintenance. These data demonstrate that multiple effector mechanisms including H2A ubiquitination and chromatin compaction combine to mediate PRC1-dependent repression of genes that are crucial for the maintenance of ESC identity. Utilization of these diverse effector mechanisms might provide a means to maintain a repressive state that is robust yet highly responsive to developmental cues during ES cell self-renewal and differentiation.
Highlights
Embryonic stem cells (ESCs) can undergo unlimited selfrenewal while maintaining their pluripotent and undifferentiated states, features that are consistent with their origin within the inner cell mass of the blastocyst
In the widely accepted hierarchical model, PRC2 is recruited to specific genomic locations and catalyzes trimethylation of H3 lysine 27 (H3K27me3), thereby creating binding sites for PRC1, which catalyzes mono-ubiquitination of histone H2A (H2AK119u1)
These genes are the central targets of Polycomb silencing to maintain embryonic stem cells (ESCs) identity
Summary
Embryonic stem cells (ESCs) can undergo unlimited selfrenewal while maintaining their pluripotent and undifferentiated states, features that are consistent with their origin within the inner cell mass of the blastocyst. Increasing evidence suggests that in addition to the core gene regulatory circuitry composed of Oct3/ 4, Sox, Nanog and other transcription factors, Polycomb group proteins critically contribute to maintain the undifferentiated state of ESCs by silencing genes that are involved in development and/ or transcription [1,2,3,4,5,6]. Polycomb group proteins are chromatin-modifiers that mediate transcriptional repression. They form at least two types of multimeric complexes, the Polycomb repressive complexes-1 (PRC1) and -2 (PRC2), the core components of which are conserved from Drosophila to human [10,11,12,13,14].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
