H2A monoubiquitination: insights from human genetics and animal models

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.

Automated summary

Metazoan development depends on the spatiotemporal control of gene expression, which is regulated by epigenetic regulators called polycomb group proteins (PcG). PcG proteins control gene expression, cell fate decisions, cell cycle progression, and DNA damage repair by adding or removing histone 2A monoubiquitination at lysine 119 (H2AK119ub1). Dysfunction of PcG genes is associated with developmental disorders, as their pathogenic variants disrupt essential developmental mechanisms. This review discusses the clinical manifestations of pathogenic PcG gene variants, their molecular functions during development, and summarizes the current understanding of the genetic and molecular mechanisms.