H2A monoubiquitination: insights from human genetics and animal models

• Published in: Human genetics Vol. 143; no. 4; pp. 511 - 527
• Main Authors: Ryan, Charles W., Peirent, Emily R., Regan, Samantha L., Guxholli, Alba, Bielas, Stephanie L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2024; Springer Nature B.V
• Subjects: Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Cell cycle; Cell fate; Chromatin; Chromatinopathies; Developmental disabilities; Disease Models, Animal; DNA damage; DNA repair; Epigenesis, Genetic; Epigenetics; Gene expression; Gene Function; Histones; Histones - genetics; Histones - metabolism; Human Genetics; Humans; Metabolic Diseases; Molecular Medicine; Molecular modelling; Polycomb group proteins; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Proteins; Review; Ubiquitination
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-023-02557-x

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.