Smarcb1 Loss Results in a Deregulation of esBAF Binding and Impacts the Expression of Neurodevelopmental Genes

Abstract

The murine esBAF complex plays a major role in the regulation of gene expression during stem cell development and differentiation. As one of its core subunits, Smarcb1 is indispensable for its function and its loss is connected to neurodevelopmental disorders and participates in the carcinogenesis of entities such as rhabdoid tumours. We explored how Smarcb1 regulates gene programs in murine embryonic stem cells (mESC) and in this way orchestrates differentiation. Our data underline the importance of Smarcb1 expression and function for the development of the nervous system along with basic cellular functions, such as cell adhesion and cell organisation. Using ChIP-seq, we were able to portray the consequences of Smarcb1 knockdown (kd) for the binding of esBAF and PRC2 as well as its influence on histone marks H3K27me3, H3K4me3 and H3K27ac. Their signals are changed in gene and enhancer regions of genes connected to nervous system development and offers a plausible explanation for changes in gene expression. Further, we describe a group of genes that are, despite increased BAF binding, suppressed after Smarcb1 kd by mechanisms independent of PRC2 function.

Role of brahma-related gene 1/brahma-associated factor subunits in neural stem/progenitor cells and related neural developmental disorders

“…Increased progenitor proliferation can result from BAF53A’s continued expression[ 46 ]. These miRNAs have an interacting location in the 3′UTR of BAF53A, and their expression is constrained in progenitors by REST and its corepressors[ 47 ]. As a result of decreased chromatin accessibility at particular neural transcription factor-binding sites brought on by BAF53A loss, cell cycle-related genes are repressed, preventing the advancement of the cell cycle and cell differentiation[ 48 ].…”

BAF45D-binding to HOX genes was differentially targeted in H9-derived spinal cord neural stem cells

“…During an in vitro motor neuron differentiation system that recapitulates embryonic development, the genomic binding profiles of different HOX genes are diverse, driving the diversification of neural patterning 8 . The BRG1/BRM-associated factor (BAF) complex, the mammalian chromatin remodeller, modulates chromatin accessibility to activate and/or repress target genes 9 , 10 . For example, rapid BAF depletion has been reported to redistribute chromatin regulators, such as the Polycomb Repressive Complexes (PRCs), from highly occupied Hox genes to weakly occupied genes, which are typically counteracted by the BAF complex 11 .…”