RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease

Abstract

During mammalian neurodevelopment, signaling pathways converge upon transcription factors (TFs) to establish appropriate gene expression programmes leading to the production of distinct neural and glial cell types. This process is partially regulated by the dynamic modulation of chromatin states by epigenetic systems, including the polycomb group (PcG) family of co-repressors. PcG proteins form multi-subunit assemblies that sub-divide into distinct, yet functionally related families. Polycomb repressive complexes 1 and 2 (PRC1 and 2) modify the chemical properties of chromatin by covalently modifying histone tails via H2A ubiquitination (H2AK119ub1) and H3 methylation, respectively. In contrast to the PRCs, the Polycomb repressive deubiquitinase (PR-DUB) complex removes H2AK119ub1 from chromatin through the action of the C-terminal hydrolase BAP1. Genetic screening has identified several PcG mutations that are causally associated with a range of congenital neuropathologies associated with both localised and/or systemic growth abnormalities. As PRC1 and PR-DUB hold opposing functions to control H2AK119ub1 levels across the genome, it is plausible that such neurodevelopmental disorders arise through a common mechanism. In this review, we will focus on advancements regarding the composition and opposing molecular functions of mammalian PRC1 and PR-DUB, and explore how their dysfunction contributes to the emergence of neurodevelopmental disorders.

Polycomb-associated and Trithorax-associated developmental conditions – phenotypic convergence and heterogeneity

“…Chromatin remodelling is a fundamental epigenetic mechanism that orchestrates development and maintains the stability of differentiated tissues. Polycomb group (PcG) and Trithorax group (TrxG) multisubunit complexes have key roles in chromatin remodelling, and act antagonistically to regulate chromatin accessibility by inducing the repression and activation of gene expression respectively 1,2 . PcG complexes mediate transcriptional repression by promoting nucleosomal compaction, as well as deterring TrxG action 1,3,4 .…”

“…It is plausible that phenotypic similarities across conditions are due to epigenomic dysregulation at shared genomic loci and at similar developmental stages, leading to downstream effects on gene expression that affect convergent developmental pathways. However, there are also phenotypic divergences within this group: for example, opposing features relating to growth have been observed amongst PcG-related conditions arising from variants in PRC1, PRC2 and PR-DUB complex genes 2,5 . Phenotypic descriptions of each MDEM in isolation may not fully capture the extent of overlap or distinctiveness between conditions, and may underplay the extent of variability within each condition.…”