Is histone H2B deubiquitylation via ATXN7L3-dependent enzymes a new mechanism disrupted in neurodevelopmental disorders?

Abstract Neurodevelopmental disorders are lifelong debilitating conditions that affect cognition and originate during embryonic development. Being heterogeneous and with a variety of etiologies, most of these disorders have no targeted treatment or cures, due to our lack of knowledge on the underlying molecular mechanisms disrupted in their pathogenesis. An emerging epigenetic mechanism recently associated with neurodevelopmental disorders is ubiquitylation of histone H2B. This posttranslational modification controls gene expression during neurodevelopment, where histone H2B ubiquitylation levels are tightly regulated by multiple deubiquitylase protein complexes ensuring correct gene expression. Components of deubiquitylase complexes regulating histone H2B ubiquitylation are the protein scaffolds ATXN7L3 and ENY2, and the deubiquitylating enzymes USP22, USP27X, and USP51. Recent clinical studies have highlighted a potential role of H2B ubiquitylation in human neurodevelopment, including the identification of neurodevelopmental disorders associated with gene variants in the ATXN7L3 , USP27X and USP51 genes. Here, we summarize our knowledge of the functions of deubiquitylase complexes that regulate histone H2B ubiquitylation and their components in neurodevelopment, and describe ATXN7L3 , USP27X , and USP51 -associated disorders, proposing future directions on the required research on their fundamental biology that could lead to targeted therapies.