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Regulation, functions and transmission of bivalent chromatin during mammalian development

Abstract

Cells differentiate and progress through development guided by a dynamic chromatin landscape that mediates gene expression programmes. During development, mammalian cells display a paradoxical chromatin state: histone modifications associated with gene activation (trimethylated histone H3 Lys4 (H3K4me3)) and with gene repression (trimethylated H3 Lys27 (H3K27me3)) co-occur at promoters of developmental genes. This bivalent chromatin modification state is thought to poise important regulatory genes for expression or repression during cell-lineage specification. In this Review, we discuss recent work that has expanded our understanding of the molecular basis of bivalent chromatin and its contributions to mammalian development. We describe the factors that establish bivalency, especially histone-lysine N-methyltransferase 2B (KMT2B) and Polycomb repressive complex 2 (PRC2), and consider evidence indicating that PRC1 shapes bivalency and may contribute to its transmission between generations. We posit that bivalency is a key feature of germline and embryonic stem cells, as well as other types of stem and progenitor cells. Finally, we discuss the relevance of bivalent chromtin to human development and cancer, and outline avenues of future research.

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Fig. 1: Overview of the establishment and maintenance of bivalent chromatin.
Fig. 2: Maintenance versus resolution of bivalency following cell divisions and differentiation.
Fig. 3: Molecular mechanisms regulating bivalent chromatin during early mouse development.

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Acknowledgements

The authors thank B. Bernstein, R. Klose, B. Lesch, M. Sachs and reviewers for critical reading of the manuscript, as well as members of the Santos laboratory for discussions and feedback (especially B. Cho, G. Furlan and S. McClymont). The authors apologize to authors whose work they did not cite owing to space constraints or oversight on their part. The original Figs. 1 and 2 were created with BioRender. T.A.M. was supported by the UCSF Medical Scientist Training Program during manuscript preparation. J.F.-R. is supported by the Lunenfeld-Tanenbaum Research Institute Studentships at Sinai Health System. Research in the Santos laboratory is supported by the Canada 150 Research Chair in Developmental Epigenetics and project grant 420231 from the Canadian Institutes of Health Research.

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All authors wrote and edited the manuscript. T.A.M. and J.F.-R. created the original figures. T.A.M. performed data analysis.

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Glossary

Epiblast

A developmental stage; the source of pluripotent cells. In the mouse, the epiblast arises approximately embryonic day 4.5 (E4.5) and persists to E7.5; in humans, this period corresponds to approximately E7–E9.

Primordial germ cells

(PGCs). Germline cells, precursors of the sex-specific gametes (oocytes and sperm).

Polycomb response elements

Sequences in fruitfly genomes that recruit Polycomb factors. They are also referred to as ‘Polycomb/Trithorax response elements’, as Trithorax proteins tend to concentrate at the same sequences.

Epigenetic priming factors

Proteins involved in establishing chromatin states conducive to transcriptional programmes for later developmental stages.

Zygotic genome activation

(ZGA). A period in early embryogenesis when transcription from the embryonic genome becomes the predominant source of transcripts in the embryo.

Pluripotency

A term that describes the ability of certain cells to generate all germ layers (mesoderm, endoderm, ectoderm and germ line) of the embryo proper. Pluripotency is perpetuated indefinitely in embryonic stem cells in vitro but occurs transiently in the embryo around implantation.

2i

Culture medium that includes inhibitors of MEK and glycogen synthase kinase 3β (GSK3β) together with leukaemia inhibitory factor (LIF), which promote a ‘ground state’ of cell pluripotency correlating with the pre-implantation mouse embryo.

Serum

Culture medium that includes fetal bovine serum and leukaemia inhibitory factor (LIF), which promote a state of pluripotency with beginning stages of lineage gene expression.

Primed

Refers to pluripotent cells (mouse or human) that display transcriptional, chromatin and developmental similarities to the post-implantation embryo.

Totipotency

Refers to the ability of cells to generate all embryonic and extra-embryonic tissues.

Inner cell mass

Cells that cluster in the inner part of the pre-implantation embryo, which give rise to the embryo proper and to fetal contributions to the extra-embryonic tissues.

Implantation

Developmental stage in which the eutherian embryo attaches to the wall of the uterus, roughly corresponding to embryonic day 4.5 in mice and a window beginning at embryonic day 6 in humans.

Naive

Refers to pluripotent cells (mouse or human) that display transcriptional, chromatin and developmental similarities to the pre-implantation embryo.

Polycomb domains

Gene-repressive domains marked by trimethylated histone H3 Lys27 and monoubiquitylated histone H2A Lys119 that tend to be heritable through cell divisions. These domains are bound by chromobox (CBX) proteins (part of canonical Polycomb repressive complex 1) that nucleate chromatin compaction.

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Macrae, T.A., Fothergill-Robinson, J. & Ramalho-Santos, M. Regulation, functions and transmission of bivalent chromatin during mammalian development. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00518-2

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