The phenomenal epigenome in neurodevelopmental disorders

Abstract

Disruption of chromatin structure due to epimutations is a leading genetic etiology of neurodevelopmental disorders, collectively known as chromatinopathies. We show that there is an increasing level of convergence from the high diversity of genes that are affected by mutations to the molecular networks and pathways involving the respective proteins, the disrupted cellular and subcellular processes, and their consequence for higher order cellular network function. This convergence is ultimately reflected by specific phenotypic features shared across the various chromatinopathies. Based on these observations, we propose that the commonly disrupted molecular and cellular anomalies might provide a rational target for the development of symptomatic interventions for defined groups of genetically distinct neurodevelopmental disorders.

Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures

“…Chromatin perturbations associated to mutations in neurodevelopmental genes damage vulnerable brain processes such as cognition development and neuronal homeostasis [ 2 , 3 ]. Notably, in patient-derived LCLs with mutations in KDM5C , ARX , PHF8 , and ZNF711 , we detected aberrant dosage of KDM5C and H3K4me3.…”

“…Brain development and neuronal differentiation are complex processes involving spatio-temporal changes in chromatin remodeling and transcriptional activity in specific brain regions and neural cell types [ 1 , 2 , 3 ]. Alterations in regulatory genes of chromatin remodeling and transcription factors (TFs) cause a huge spectrum of neurodevelopmental disorders (NDDs) [ 2 , 4 , 5 , 6 ].…”

The Epigenome in Neurodevelopmental Disorders

“…Changes in epigenomic signatures are suggested to be acquired de novo on chromatin but are also discussed to be inheritable, passing from one generation to the next, which is reported for Caenorhabditis elegans or mice ( Morgan et al, 1999 ; Gaydos et al, 2014 ; Wei et al, 2014 ). In humans, different suggestions debate the problem whether the genetic background of patients causes NDDs, or whether environmental stimuli increase the risk of improper brain development ( Buiting et al, 2003 ; Mastrototaro and Sessa, 2018 ; Ciptasari and van Bokhoven, 2020 ; Cristancho and Marsh, 2020 ). In this section, we provide an overview of different epigenetic mechanisms governing neurodevelopmental processes, which are suggested to be associated with NDDs and MCDs, and to be responsive to “environmental insults.”…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…With the use of sophisticated diagnostic tools such as whole exome sequencing and whole genome sequencing, the number of genes and variants linked to the aetiology of NDDs is vastly increasing [ 7 , 8 ]. By doing so, chromatin remodelling genes have been found enriched in large datasets of NDD patients, and thereby pointing towards epigenetics as a convergent pathogenic mechanism [ 8 – 13 ]. By altering the epigenetic state of genes or histones, chromatin remodelers play an integral part in the machinery that translate external signals into lasting changes in gene expression patterns [ 14 ].…”