Abstract
It is becoming increasingly important to understand how epigenetic mechanisms control gene expression during neurodevelopment. Two epigenetic mechanisms that have received considerable attention are DNA methylation and histone acetylation. Human exome sequencing and genome-wide association studies have linked several neurobiological disorders to genes whose products actively regulate DNA methylation and histone acetylation. More recently, a third major epigenetic mechanism, nucleosome remodeling, has been implicated in human developmental and intellectual disability (ID) disorders. Nucleosome remodeling is driven primarily through nucleosome remodeling complexes with specialized ATP-dependent enzymes. These enzymes directly interact with DNA or chromatin structure, as well as histone subunits, to restructure the shape and organization of nucleosome positioning to ultimately regulate gene expression. Of particular interest is the neuron-specific Brg1/hBrm Associated Factor (nBAF) complex. Mutations in nBAF subunit genes have so far been linked to Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NBS), schizophrenia, and Autism Spectrum Disorder (ASD). Together, these human developmental and ID disorders are powerful examples of the impact of epigenetic modulation on gene expression. This review focuses on the new and emerging role of nucleosome remodeling in neurodevelopmental and ID disorders and whether nucleosome remodeling affects gene expression required for cognition independently of its role in regulating gene expression required for development.
Highlights
It has long been understood that gene expression is critical for neural development, and for healthy cognition in the adult
In this review we have focused on the role of nucleosome remodeling in development and adult cognition
Several human sequencing studies have shown that mutations in the genes making up the Brm-associated factor (BAF) complex in particular may give rise to distinct intellectual disability (ID) disorders including Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NBS), and Autism Spectrum Disorder (ASD)
Summary
It has long been understood that gene expression is critical for neural development, and for healthy cognition in the adult. Nucleosomes are the basic subunit of chromatin and consist of approximately 147 DNA base pairs spooled around a histone octamer These nucleosomes can fluctuate between various levels of compaction, and their state is a critical and limiting factor in allowing transcription machinery to access genes of interest. Nucleosome remodeling in developmental neuroepigenetic disorders coordinate large protein complexes for transcriptional regulation These activities have a major role in both where and when necessary genes are expressed (Barrett and Wood, 2008; Hargreaves and Crabtree, 2011; Rando and Winston, 2012). Such epigenetic mechanisms include DNA methylation, histone modifications (including acetylation, ubiquitination, and phosphorylation), and nucleosome remodeling. Chromatin modification has two primary functions including the regulation of DNA-histone interaction as well as serving as a signal transduction integration platform for coordinate gene regulation (Barrett and Wood, 2008)
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