The dynamics of chromatin architecture in brain development and function

Sex-specific multi-level 3D genome dynamics in the mouse brain

“…3D genome organization allows orderly interactions of physically-distant parts of the genome and is thought to play a critical role in gene regulation and cellular function across organs and disease states (15,17). 3D genome remodeling has only recently been implicated in brain development (18) and function (19,20), neuronal activity-dependent gene regulation (21,22), and memory formation (23)(24)(25)(26). However, previous 3D genome studies of the brain were either focused on the male brain or did not explore sex differences.…”

“…Three-dimensional (3D) genome organization allows interactions of genes with their distant cis-regulatory elements, through chromatin looping and compartmentalization, and is thought to play a major role in transcriptional regulation (15)(16)(17). Within the brain, 3D genome remodeling has only recently been implicated in neuronal differentiation (18) and function (19,20), neuronal activity-dependent gene regulation (21,22), and memory formation (23)(24)(25)(26), but whether there are sex differences and sex hormone-mediated influences on this regulation remains unknown.…”

How can same-gene mutations promote both cancer and developmental disorders?

“…These include histone demethylation, and the recognition of DNA methylation ( 102 , 103 ) and promoter architecture reorganization during neuronal cell differentiation implicates target genes for neurodevelopmental disorders ( 104 ). Remodeling can affect regulatory regions of distal genes via long-range chromatin interactions, in a cell type–, developmental stage–, and disease-specific manner ( 105 ). Variants of mediator MED12 subunit, with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation, have also been linked to neurodevelopmental disorders ( 106 ).…”

Retrotransposons as Drivers of Mammalian Brain Evolution

“…A few described cases of human-specific changes in gene expression patterns that are important for brain development include those affecting the enhancers of neuronal PAS domain protein 3 ( NPAS3 ), encoding a TF involved in neurogenesis [ 171 ], frizzled class receptor 8 ( FZD8 ), coding for a Wnt protein receptor involved in neocortex development [ 172 ], osteocrin ( OSTN ), encoding an activity-dependent secreted factor [ 173 ], cut-like homeobox 1 ( CUX1 ), encoding a TF involved in dendritic development and implicated in autism spectrum disorder [ 170 ], and fibroblast growth factor receptor 2 ( FGFR2 ) [ 174 ]. Enhancer–promoter interactions, that are key to the implementation of gene-regulatory programs, take place in the context of a complex and dynamic 3D chromatin architecture, of which the involvement in brain development, neuronal activity and complex brain disorders is only starting to be appreciated [ 175 , 176 ]. Based on these premises, it is not unexpected that brain evolutionary innovations have occurred through the 3D rewiring of the enhancer–promoter interactome, as very recently revealed for primate corticogenesis [ 14 ].…”