Jarid2 Methylation via the PRC2 Complex Regulates H3K27me3 Deposition during Cell Differentiation

Serena Sanulli,Neil Justin,Aurélie Teissandier,Katia Ancelin,Manuela Portoso,Matthieu Caron,Audrey Michaud,Berangère Lombard,Simao T Da Rocha,John Offer,Damarys Loew,Nicolas Servant,Michel Wassef,Fabienne Burlina,Steve J Gamblin,Edith Heard,Raphaël Margueron

doi:10.1016/j.molcel.2014.12.020

Abstract

SummaryPolycomb Group (PcG) proteins maintain transcriptional repression throughout development, mostly by regulating chromatin structure. Polycomb Repressive Complex 2 (PRC2), a component of the Polycomb machinery, is responsible for the methylation of histone H3 lysine 27 (H3K27me2/3). Jarid2 was previously identified as a cofactor of PRC2, regulating PRC2 targeting to chromatin and its enzymatic activity. Deletion of Jarid2 leads to impaired orchestration of gene expression during cell lineage commitment. Here, we reveal an unexpected crosstalk between Jarid2 and PRC2, with Jarid2 being methylated by PRC2. This modification is recognized by the Eed core component of PRC2 and triggers an allosteric activation of PRC2’s enzymatic activity. We show that Jarid2 methylation is important to promote PRC2 activity at a locus devoid of H3K27me3 and for the correct deposition of this mark during cell differentiation. Our results uncover a regulation loop where Jarid2 methylation fine-tunes PRC2 activity depending on the chromatin context.

Highlights

Appropriate gene expression patterns in distinct cell lineages need to be set during embryogenesis and perpetuated during the lifespan of an organism
We recently demonstrated that Jarid2 has a nucleosome-binding domain that stabilizes Polycomb Repressive Complex 2 (PRC2) binding to chromatin (Son et al, 2013), interaction that could be modulated by long non-coding RNAs (lncRNAs) (Kaneko et al, 2014)
By performing Lysine Methyl-Transferase (KMT) assays in vitro with PRC2 and Jarid2, we observed that Jarid2 is methylated by PRC2 both when this complex is reconstituted around Ezh2 or Ezh1 (Figure S1A)

Summary

Introduction

Appropriate gene expression patterns in distinct cell lineages need to be set during embryogenesis and perpetuated during the lifespan of an organism. A first ‘‘instructive’’ model proposes that PRC2 recruitment relies either on transcription factors (TFs) or on long non-coding RNAs (lncRNAs). Several studies support this hypothesis, with the examples of the lncRNAs Xist (Maenner et al, 2010; Zhao et al, 2008), HOTAIR (Rinn et al, 2007), or Kcnq1ot (Pandey et al, 2008; Redrup et al, 2009) and of TFs such as YY1 (Palacios et al, 2010; Woo et al, 2010, 2013) or Snail (Herranz et al, 2008). The nature and the relevance of the interactions between PRC2 and lncRNAs or TFs are not yet clear (Brockdorff, 2013)

Results

Discussion

Conclusion