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H2A monoubiquitination: insights from human genetics and animal models

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Abstract

Metazoan development arises from spatiotemporal control of gene expression, which depends on epigenetic regulators like the polycomb group proteins (PcG) that govern the chromatin landscape. PcG proteins facilitate the addition and removal of histone 2A monoubiquitination at lysine 119 (H2AK119ub1), which regulates gene expression, cell fate decisions, cell cycle progression, and DNA damage repair. Regulation of these processes by PcG proteins is necessary for proper development, as pathogenic variants in these genes are increasingly recognized to underly developmental disorders. Overlapping features of developmental syndromes associated with pathogenic variants in specific PcG genes suggest disruption of central developmental mechanisms; however, unique clinical features observed in each syndrome suggest additional non-redundant functions for each PcG gene. In this review, we describe the clinical manifestations of pathogenic PcG gene variants, review what is known about the molecular functions of these gene products during development, and interpret the clinical data to summarize the current evidence toward an understanding of the genetic and molecular mechanism.

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Acknowledgements

This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human development (R01AWD010411 to SLB), National Institute of Neurological Disorders and Stroke (R01NS101597 to SLB), Leo's Lighthouse Foundation to SLB, NIH Cellular and Molecular Biology Training Grant (T32-GM007315 to CWR), NRSA Fellowship Grant (F31NS127551 to CWR), MSTP (T32GM007863 to CWR), and Neuroscience training grant (T32-NS076401 to ERP).

Funding

This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human development (R01AWD010411 to SLB), National Institute of Neurological Disorders and Stroke (R01NS101597 to SLB), Leo's Lighthouse Foundation to SLB, NIH Cellular and Molecular Biology Training Grant (T32-GM007315 to CWR), NRSA Fellowship Grant (F31NS127551 to CWR), MSTP (T32GM007863 to CWR), and Neuroscience training grant (T32-NS076401 to ERP).

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Authors and Affiliations

  1. Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, 48109-5618, USA

    Charles W. Ryan & Stephanie L. Bielas

  2. Medical Science Training Program, University of Michigan Medical School, 3703 Med Sci II, 1241 E. Catherine St., Ann Arbor, MI, 48109-5618, USA

    Charles W. Ryan

  3. Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI, 48109-5618, USA

    Emily R. Peirent & Stephanie L. Bielas

  4. Department of Human Genetics, University of Michigan Medical School, 3703 Med Sci II, 1241 E. Catherine St., Ann Arbor, MI, 48109-5618, USA

    Samantha L. Regan, Alba Guxholli & Stephanie L. Bielas

  5. Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, 48199-5618, USA

    Alba Guxholli & Stephanie L. Bielas

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  1. Charles W. Ryan
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Correspondence to Stephanie L. Bielas.

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Ryan, C.W., Peirent, E.R., Regan, S.L. et al. H2A monoubiquitination: insights from human genetics and animal models. Hum. Genet. 143, 511–527 (2024). https://doi.org/10.1007/s00439-023-02557-x

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