Regulation of Genome Architecture and Function by Polycomb Proteins

doi:10.1016/j.tcb.2016.04.009

Trends in Cell Biology

Volume 26, Issue 7, July 2016, Pages 511-525

https://doi.org/10.1016/j.tcb.2016.04.009 Get rights and content

Trends

Nuclear architecture is not only important for the efficient compaction and decompaction of the genome during cell division, but has important functions in coordinating gene regulatory networks and orchestrating cellular identity.

Changes in nuclear organization are considered an important complement to epigenetic mechanisms contributing to robust and stable gene silencing.

Recruitment of Polycomb group (PcG) proteins to their target sites not only modulates local chromatin structure but also mediates looping interactions between regulatory elements and shapes global nuclear architecture, thereby regulating gene expression at multiple scales.

The evolutionarily conserved PcG proteins regulate cell identity and cell differentiation by orchestrating 3D genome architecture.

Polycomb group (PcG) proteins dynamically define cellular identities through the epigenetic repression of key developmental regulatory genes. PcG proteins are recruited to specific regulatory elements to modify the chromatin surrounding them. In addition, they regulate the organization of their target genes in the 3D space of the nucleus, and this regulatory function of the 3D genome architecture is involved in cell differentiation and the maintenance of cellular memory. In this review we discuss recent advances in our understanding of how PcG proteins are recruited to chromatin to induce local and global changes in chromosome conformation and regulate their target genes.

Section snippets

PcG Proteins in Cell Identity, Epigenetic Gene Regulation, and Chromatin Architecture

The capacity to generate different cell identities from an identical genome sequence, such as that of the single-cell zygote, relies on the establishment of cell type-specific expression programs that are maintained during development, even in the absence of the original initiating transcription factors (TFs), by so-called epigenetic (see Glossary) mechanisms [1]. Various modes of epigenetic gene regulation are used to fix transcriptional programs in time and space. These include DNA

Structural and Functional Diversity of PcG Proteins

PcG genes were originally identified from mutations that induce homeotic transformations dependent on ectopic expression of homeotic (HOX) genes 4, 5. Since then, a large number of studies have shown that PcG proteins can dynamically regulate many genes that play key roles in the regulation of cellular processes including cell identity, cell fate choices, cell cycle control, cellular senescence, genomic imprinting, stem cell plasticity, and cellular transformation leading to cancer [6]. This

Recruitment of PcG Complexes to Chromatin

Understanding how PcG complexes are recruited to DNA has been a hot topic for many years and many gaps remain in our knowledge (see Outstanding Questions).

Gene Repression by PcG Proteins Involves Multiple Layers of Chromatin Organization

PcG complexes can repress their target genes via multiple non-mutually exclusive mechanisms and chromatin organization levels.

Concluding Remarks

Since the discovery of PcG proteins four decades ago, the spectrum of PcG function has not stopped growing. Consistent with the huge functional diversity of PcG proteins, biochemical studies have shown a greater diversity of PcG complexes than was originally anticipated. PcG complexes can employ various mechanisms to find their chromosomal targets. An intriguing, but yet to be tested, hypothesis is that different PcG complexes might use different target sequences and mechanisms to find their

Acknowledgments

The authors thank Thomas Sexton (IGBMC, France) for critically reading the manuscript. Research in the laboratory of G.C. was supported by grants from the European Research Council (ERC-2008-AdG No 232947), the European H2020 EINFRA MuG grant, the CNRS, the INSERM, the European Network of Excellence EpiGeneSys, the Agence Nationale de la Recherche (EpiDevoMath), the MMTT grant of the ITMO Cancer and INSERM, and the Laboratory of Excellence EpiGenMed. M.E. was supported by the French Ministry of

Glossary

Chromosome conformation capture (3C)-derived techniques: 3C is a high-throughput molecular biology technique used to study chromatin structure. 3C provides information about the interaction frequencies of DNA sequences therefore providing information on 3D genome structure.
CpG islands (CGIs): short interspersed DNA sequences that have a high density of CpG dinucleotides and are predominantly non-methylated. In vertebrates, most CGIs map to promoters.
Embryonic stem cells (ESCs): pluripotent stem cells

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Polycomb Group proteins regulate gene expression by modifying chromatin. Polycomb Repressive Complex 1 (PRC1) has two activities: a ubiquitin ligase activity for histone H2A and a chromatin compacting activity. In Drosophila, the Posterior Sex Combs (PSC) subunit of PRC1 is central to both activities. The N-terminal of PSC assembles into PRC1, including partnering with dRING to form the ubiquitin ligase. The intrinsically disordered C-terminal region of PSC compacts chromatin and inhibits chromatin remodeling and transcription in vitro. Both regions of PSC are essential in vivo. To understand how these two activities may be coordinated in PRC1, we used crosslinking mass spectrometry to analyze the conformations of the C-terminal region of PSC in PRC1 and how they change on binding DNA. Crosslinking identifies interactions between the C-terminal region of PSC and the core of PRC1, including between N and C-terminal regions of PSC. New contacts and overall more compacted PSC C-terminal region conformations are induced by DNA binding. Protein footprinting of accessible lysine residues reveals an extended, bipartite candidate DNA/chromatin binding surface in the C-terminal region of PSC. Our data suggest a model in which DNA (or chromatin) follows a long path on the flexible disordered region of PSC. Intramolecular interactions of PSC detected by crosslinking can bring the high-affinity DNA/chromatin binding region close to the core of PRC1 without disrupting the interface between the ubiquitin ligase and the nucleosome. Our approach may be applicable to understanding the global organization of other large intrinsically disordered regions that bind nucleic acids.

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Trends in Cell Biology

ReviewSpecial Issue: 25 Years of Trends in Cell BiologyRegulation of Genome Architecture and Function by Polycomb Proteins

Trends

Section snippets

PcG Proteins in Cell Identity, Epigenetic Gene Regulation, and Chromatin Architecture

Structural and Functional Diversity of PcG Proteins

Recruitment of PcG Complexes to Chromatin

Gene Repression by PcG Proteins Involves Multiple Layers of Chromatin Organization

Concluding Remarks

Acknowledgments

Glossary

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Mol. Cell Proteomics

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Mol. Cell

Curr. Opin. Genet. Dev.

Cell

Transcriptional regulation by Polycomb group proteins

Nat. Struct. Mol. Biol.

A gene complex controlling segmentation in Drosophila

Nature

Polycomblike: a gene that appears to be required for the normal expression of the bithorax and antennapedia gene complexes of Drosophila melanogaster

Genetics

Recruitment of Polycomb group complexes and their role in the dynamic regulation of cell fate choice

Development

Regulation of gene transcription by Polycomb proteins

Sci. Adv.

Role of histone H2A ubiquitination in Polycomb silencing

Nature

Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains

Genes Dev.

Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27

Genes Dev.

YY1 DNA binding and interaction with YAF2 is essential for Polycomb recruitment

Nucleic Acids Res.

Polycomb group protein Suppressor 2 of zeste is a functional homolog of Posterior Sex Combs

Mol. Cell Biol.

dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group silencing

Genes Dev.

Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets

Mol. Cell Biol.

Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity

EMBO J.

A model for transmission of the H3K27me3 epigenetic mark

Nat. Cell Biol.

Role of the Polycomb protein EED in the propagation of repressive histone marks

Nature

Molecular architecture of human Polycomb repressive complex 2

Elife

Review
Special Issue: 25 Years of Trends in Cell Biology
Regulation of Genome Architecture and Function by Polycomb Proteins