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Context-specific Polycomb mechanisms in development

Nature Reviews Genetics volume 23, pages 680–695 (2022)Cite this article

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Abstract

Polycomb group (PcG) proteins are crucial chromatin regulators that maintain repression of lineage-inappropriate genes and are therefore required for stable cell fate. Recent advances show that PcG proteins form distinct multi-protein complexes in various cellular environments, such as in early development, adult tissue maintenance and cancer. This surprising compositional diversity provides the basis for mechanistic diversity. Understanding this complexity deepens and refines the principles of PcG complex recruitment, target-gene repression and inheritance of memory. We review how the core molecular mechanism of Polycomb complexes operates in diverse developmental settings and propose that context-dependent changes in composition and mechanism are essential for proper epigenetic regulation in development.

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Fig. 1: Composition and molecular functions of Polycomb complexes.
Fig. 2: Formation of repressed domains by positive feedback between Polycomb complexes.
Fig. 3: Examples of cell type-specific Polycomb complexes.
Fig. 4: Redistribution of Polycomb complexes.
Fig. 5: Hypothetical models of the different roles of Polycomb complexes in the maintenance of gene repression.

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Acknowledgements

The authors thank J. Zhu, M. Mauger, E. Steinson, J. Wucherpfennig, U. Cho and E. Grow for critical reading of the manuscript. This work was supported by NIH grant R35-GM131743 to R.E.K.

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  1. Department of Molecular Biology and MGH Research Institute, Massachusetts General Hospital, Boston, MA, USA

    Jongmin J. Kim & Robert E. Kingston

  2. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Jongmin J. Kim & Robert E. Kingston

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Glossary

Homeotic transformation

A class of mutant phenotypes in which a body segment transforms into another body segment, usually as a result of misregulation of Hox genes. A classic example is the Antennapedia mutation in Drosophila melanogaster, which results in legs instead of antennae.

Paralogous

Paralogous genes are derived from an ancestral gene by gene duplication events within the same species. Paralogous proteins can retain similar functions, but they can also acquire distinct functions.

Preimplantation embryos

Placental animal embryos from zygote to before implantation stages. The first lineage specification between inner cell mass (which gives rise to embryo proper) and trophectoderm (which gives rise to the placenta) happens during this stage.

Orthologue

Orthologous genes are derived by speciation events, therefore, orthologues are present in different species. Orthologous proteins can retain similar functions, but they can also acquire distinct functions.

Nucleosome arrays

In vitro reconstituted chromatin templates used to study biochemical properties of chromatin-modifying proteins, which are made from DNA with nucleosome positioning sequences and linker mixed with histone octamers.

mSWI/SNF

A protein complex that can destabilize histone–DNA interactions in an ATP-dependent manner. It can create accessibility to DNA and counteract Polycomb-mediated repression.

Phase separation

A phenomenon whereby proteins transition to another phase with different physicochemical properties, often through multivalent interactions between themselves. It is potentially one of the driving forces in the formation of membraneless organelles and condensates in the cell.

Pericentromeres

Regions of chromosome adjacent to the centromeres, composed of AT-rich satellite DNA tandem repeats, usually DNA-methylated and methylated at lysine 9 of histone H3.

CpG islands

Approximately 1 kb DNA regions in vertebrates with overrepresentation of CpG dinucleotides compared with the genome average. They are often a site of transcription initiation, and more than half of annotated gene promoters are CpG islands.

Polycomb response element

(PRE). Discrete regulatory DNA element that can nucleate recruitment of Polycomb complexes and silencing in Drosophila melanogaster.

Vernalization

A process of prolonged exposure to the cold that induces flowering in plants. Genetic screens to find genes required for vernalization uncovered several genes later identified to be part of plant Polycomb complexes.

Trithorax group

(trxG). A group of chromatin regulators that maintains an active state of gene expression that includes mSWI/SNF complex. Genes encoding trxG proteins were originally discovered by a genetic suppression screen in Drosophila melanogaster to suppress the Polycomb mutant phenotype.

Zygotic genome activation

After fertilization, transcription is absent in the zygotic genome, therefore, embryos develop with maternally provided transcripts. Zygotic genome activation happens as maternal mRNA decays, and genes are transcribed from the zygotic genome through the process called maternal-to-zygotic transition.

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Kim, J.J., Kingston, R.E. Context-specific Polycomb mechanisms in development. Nat Rev Genet 23, 680–695 (2022). https://doi.org/10.1038/s41576-022-00499-0

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