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Capturing the onset of PRC2-mediated repressive domain formation

Ozgur Oksuz, Varun Narendra, Chul-Hwan Lee, Nicolas Descostes, Gary LeRoy, Ramya Raviram, Lili Blumenberg, Kelly Karch, Pedro R. Rocha, Benjamin A. Garcia, Jane A. Skok, Danny Reinberg

Preprint posted on February 27, 2018 https://www.biorxiv.org/content/early/2018/02/27/272989

How does Polycomb initiate and maintain gene silencing? A new preprint identifies a two-step mechanism of H3K27me2/3 domain formation – initial recruitment to spatially interacting sites followed by spreading in cis and via long-range contacts.

Selected by Boyan Bonev

Why is it important?

Lineage specification depends on the stable and faithful inheritance of gene expression profiles. Epigenetic regulation, including modification of DNA and histones, plays an important role in establishing and maintaining cell fate identity during development. Among those, Polycomb-mediated repressive chromatin state associated with H3K27me2/3 has been extensively studied and many important players have been identified. However, how Polycomb is initially recruited to specific genomic loci in mammals and how this is translated into repressive domains of H3K27me3 remains unclear.

What are the key findings?

In this preprint Reinberg and colleagues develop and employ an inducible system to study the dynamics and the determinants of the initial Polycomb Repressive Complex 2 (PRC2) recruitment and spreading in mouse embryonic stem cells. They discover that PRC2 is first deposited only at a small subset of its binding sites, which are enriched in dense CpG islands. The authors identify the proteins Jarid2 and specifically Mtf2 as essential for this initial PRC2 recruitment. Subsequently, H3K27me3 spreads from these “nucleation sites” both in cis- and via long-range 3D chromatin contacts. Importantly, a mutation in one subunit of the PRC2 complex – Eed, affects the spreading but not the initial binding of PRC2 to the nucleation sites, further suggesting that they represent two temporarily distinct events. Furthermore, using chromatin conformation capture assays they show that spreading of H3K27me3 is facilitated via long-range chromatin interactions and that contacts between “nucleation sites” are partially dependent on polycomb. Finally, using an elegant tethering system they demonstrate that PRC2 activity exploits 3D genome architecture to spread across distal, contacting regions.

Questions arising

Does the spatial clustering of polycomb-associated sites result in liquid phase-separation phenomenon?

What is the molecular mechanism for long-range loop formation between polycomb loci?

Does PRC1 complex also follow similar kinetics for its recruitment and spreading?

Related Research

Schuettengruber, B. et al. Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. Cell 171, 34-57 (2017).

Schoenfelder, S., et. al. & Elderkin, S. Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome . Nat Genetics 47, 1179-1186 (2015).

 

Tags: chromatin, epigenetics, polycomb

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