Variant PRC1 Complex-Dependent H2A Ubiquitylation Drives PRC2 Recruitment and Polycomb Domain Formation

Neil P Blackledge,Anca M Farcas,Takashi Kondo,Hamish W King,Joanna F Mcgouran,Lars L.P Hanssen,Shinsuke Ito,Sarah Cooper,Kaori Kondo,Yoko Koseki,Tomoyuki Ishikura,Hannah K Long,Thomas W Sheahan,Neil Brockdorff,Benedikt M Kessler,Haruhiko Koseki,Robert J Klose

doi:10.1016/j.cell.2014.05.004

Neil P Blackledge, Anca M Farcas + Show 15 more

Open Access

https://doi.org/10.1016/j.cell.2014.05.004

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Abstract

SummaryChromatin modifying activities inherent to polycomb repressive complexes PRC1 and PRC2 play an essential role in gene regulation, cellular differentiation, and development. However, the mechanisms by which these complexes recognize their target sites and function together to form repressive chromatin domains remain poorly understood. Recruitment of PRC1 to target sites has been proposed to occur through a hierarchical process, dependent on prior nucleation of PRC2 and placement of H3K27me3. Here, using a de novo targeting assay in mouse embryonic stem cells we unexpectedly discover that PRC1-dependent H2AK119ub1 leads to recruitment of PRC2 and H3K27me3 to effectively initiate a polycomb domain. This activity is restricted to variant PRC1 complexes, and genetic ablation experiments reveal that targeting of the variant PCGF1/PRC1 complex by KDM2B to CpG islands is required for normal polycomb domain formation and mouse development. These observations provide a surprising PRC1-dependent logic for PRC2 occupancy at target sites in vivo.

Highlights

In eukaryotic cells, chromatin structure and posttranslational modification of histone proteins play central roles in regulating gene expression
Chromatin modifying activities inherent to polycomb repressive complexes PRC1 and PRC2 play an essential role in gene regulation, cellular differentiation, and development
This activity is restricted to variant PRC1 complexes, and genetic ablation experiments reveal that targeting of the variant PCGF1/PRC1 complex by KDM2B to CpG islands is required for normal polycomb domain formation and mouse development

Summary

Introduction

Chromatin structure and posttranslational modification of histone proteins play central roles in regulating gene expression. This is exemplified in animals where polycomb group proteins function as chromatin-based transcriptional repressors through their capacity to catalyze histone modifications and form higher order chromatin structures (recently reviewed in Schwartz and Pirrotta, 2013; Simon and Kingston, 2013). The combined activities of PRC1 and PRC2 are thought to be essential for normal polycomb-mediated transcriptional repression and developmental gene regulation (recently reviewed in Simon and Kingston, 2013). The molecular mechanisms by which polycomb group proteins recognize their target sites and initiate repressive chromatin domains remain poorly defined

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Conclusion