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.

Figure 1

Simplified protein–protein interaction network of compiled chromatinopathy genes generated by StringDB (version 11.0, MCL clustering) analysis of chromatinopathy genes. For clarity, only proteins with interactions are shown. Connecting lines showing medium- and high-confidence experimental interactions (confidence > 0.400) with line thickness indicates the strength of data support.

Figure 2

Schematic representation of convergence of chromatinopathies. Individual chromatinopathy genes encode proteins that interact with each other in chromatin remodeling. These interactions cluster in chromatin remodeling complexes such as the BAF, PRC2 and COMPASS complexes, which then affect the transcription of their target genes. Aberrant transcription level of various genes in different chromatinopathies leads to commonly disrupted molecular and cellular processes, such as WNT signaling and genes involved in acute synaptic function. Disrupted WNT signaling affects proliferation of stem cells and the process of neurogenesis, which can lead to anomalies in brain development such as micro- and macrocephaly. Synaptic function and activity is an important process in brain circuits development. Imbalance of excitation and inhibitory (E/I) has emerged as a common neurophysiological mode-of-failure in ASD, ID and NDDs in general. Combination of disruption of multiple developmental processes leads to commonly shared symptoms, which in different combinations and levels of severity builds onto specific chromatinopathy syndromes and disorders.