The chromatin basis of neurodevelopmental disorders: Rethinking dysfunction along the molecular and temporal axes

Abstract

The complexity of the human brain emerges from a long and finely tuned developmental process orchestrated by the crosstalk between genome and environment. Vis à vis other species, the human brain displays unique functional and morphological features that result from this extensive developmental process that is, unsurprisingly, highly vulnerable to both genetically and environmentally induced alterations. One of the most striking outcomes of the recent surge of sequencing-based studies on neurodevelopmental disorders (NDDs) is the emergence of chromatin regulation as one of the two domains most affected by causative mutations or Copy Number Variations besides synaptic function, whose involvement had been largely predicted for obvious reasons. These observations place chromatin dysfunction at the top of the molecular pathways hierarchy that ushers in a sizeable proportion of NDDs and that manifest themselves through synaptic dysfunction and recurrent systemic clinical manifestation. Here we undertake a conceptual investigation of chromatin dysfunction in NDDs with the aim of systematizing the available evidence in a new framework: first, we tease out the developmental vulnerabilities in human corticogenesis as a structuring entry point into the causation of NDDs; second, we provide a much needed clarification of the multiple meanings and explanatory frameworks revolving around "epigenetics", highlighting those that are most relevant for the analysis of these disorders; finally we go in-depth into paradigmatic examples of NDD-causing chromatin dysregulation, with a special focus on human experimental models and datasets.

7q11.23 Syndromes Reveal BAZ1B as a Master Regulator of the Modern Human Face and Validate the Self-Domestication Hypothesis

“…Finally, a Master Regulator Analysis identified candidate regulators of BAZ1B DEGs, including 10 factors involved in enhancer marking (CEBPB, p300, RBBP5, HDAC2, KDM1A and TCF12), promoter activation (TBP, TAF1 and POL2) and chromatin remodeling (CTCF, RAD21 YY1) ( Fig. 2E; S2C), several of which are themselves causative genes of intellectual disability (ID) syndromes with neurocristopathic involvement, as in the case of our recently identified Gabrielede Vries syndrome caused by YY1 haploinsufficiency (42,43). Chromatin remodeling was indeed 15 the most prominently enriched group within the overall domain of transcriptional regulation.…”

The conserved DNMT1 dependent methylation regions in human cells are vulnerable to environmental rotenone

“…Unsurprisingly, three of these transcription factors were TAF1, TBP, and POL2RA which all have an essential role in initializing transcription. We were interested to see SIN3A and RBBP5 which both interact with histone modifying enzymes to regulate chromatin accessibility and are critical during neurodevelopment (Gabriele et al 2018). Furthermore, SIN3A is recruited to the methyl-CpG binding protein MeCP2 to silence transcription.…”

Clinical epigenetics: a primer for the practitioner

“…2,12,16 Given that the dysfunction of these molecules results in epigenetic errors affecting hundreds of genes on many different chromosomes, these disorders display a wide range of multisystemic symptoms ( Table 1). 1,18,19 Other common features of these disorders include limb malformations and immune dysfunction. Genome wide sequencing reveals that many disorders characterized by intellectual disability are caused by de novo mutations in the epigenetic machinery.…”

“…16,17 In fact, a disproportionately high number of genes related to intellectual disability encode for protein components of the epigenetic transcription regulation. 1,18,19 Other common features of these disorders include limb malformations and immune dysfunction. 2,20,21 The majority of the genes defective in disorders of the epigenetic machinery are located on autosomal chromosomes, but the rest (~20%) are X-linked.…”

“…[1][2][3][4] In recent years, clinical exome sequencing of patient's DNA has become the shiniest new tool in the geneticist's toolbox, but epigenetics has shown that we need to know more than just where the As, Cs, Ts, and Gs (nucleotides) are. Today, another scientific revolution has taken place on a new frontier: epigenetics.…”