The Epigenome in Neurodevelopmental Disorders

Abstract

Neurodevelopmental diseases (NDDs), such as autism spectrum disorders, epilepsy, and schizophrenia, are characterized by diverse facets of neurological and psychiatric symptoms, differing in etiology, onset and severity. Such symptoms include mental delay, cognitive and language impairments, or restrictions to adaptive and social behavior. Nevertheless, all have in common that critical milestones of brain development are disrupted, leading to functional deficits of the central nervous system and clinical manifestation in child- or adulthood. To approach how the different development-associated neuropathologies can occur and which risk factors or critical processes are involved in provoking higher susceptibility for such diseases, a detailed understanding of the mechanisms underlying proper brain formation is required. NDDs rely on deficits in neuronal identity, proportion or function, whereby a defective development of the cerebral cortex, the seat of higher cognitive functions, is implicated in numerous disorders. Such deficits can be provoked by genetic and environmental factors during corticogenesis. Thereby, epigenetic mechanisms can act as an interface between external stimuli and the genome, since they are known to be responsive to external stimuli also in cortical neurons. In line with that, DNA methylation, histone modifications/variants, ATP-dependent chromatin remodeling, as well as regulatory non-coding RNAs regulate diverse aspects of neuronal development, and alterations in epigenomic marks have been associated with NDDs of varying phenotypes. Here, we provide an overview of essential steps of mammalian corticogenesis, and discuss the role of epigenetic mechanisms assumed to contribute to pathophysiological aspects of NDDs, when being disrupted.

Roots of the Malformations of Cortical Development in the Cell Biology of Neural Progenitor Cells

“…Importantly, various molecules involved in the regulation of gene expression have been implicated in the emergence of MCD. Transcription factors, notably PAX6, TBR2, EMX2, FOXG1, ARX, DMRTA2, and others ( Mallamaci et al, 2000 ; Kitamura et al, 2002 ; Ligon et al, 2003 ; Baala et al, 2007 ; Asami et al, 2011 ; Baek et al, 2015 ; Urquhart et al, 2016 ), as well as epigenetic mechanisms, including histone modifications, chromatin remodeling and RNA-level regulation, have been shown to play an important role in the onset of MCDs ( Qiao et al, 2016 ; Silver, 2016 ; Albert and Huttner, 2018 ; Doan et al, 2018 ; Gabriele et al, 2018 ; Franz et al, 2019 ; Ciptasari and van Bokhoven, 2020 ; Vaid and Huttner, 2020 ; Reichard and Zimmer-Bensch, 2021 ; Wilson et al, 2021 ).…”

Editorial: Epigenetics of Neurodevelopmental, Neuromuscular and Neurodegenerative Disorders

“…Epigenetic mechanisms are fundamental for the development and function of the central nervous system, and their impairment contributes to neurodevelopmental (Reichard and Zimmer-Bensch, 2021), neuromuscular (Coppedè, 2020), and neurodegenerative disorders (Gagliardi et al, 2018;Bellver-Sanchis et al, 2021). As such, active research is ongoing to identify epigenetic biomarkers of these disorders, and both DNA methylation changes and circulating RNAs are increasingly recognized as potential biomarkers to improve diagnosis and to monitor disease status and response to therapeutic interventions (Sproviero et al, 2021;Hirunagi et al, 2022;Kaur et al, 2022).…”

Exploring epigenomic mechanisms of neural tube defects using multi‐omics methods and data

“…Histone modifications, such as acetylation, phosphorylation, methylation, ubiquitination, and sumoylation, play a significant role in the regulation of the chromatin structure 75 . Evidence gained from the study of neurodevelopmental defects indicates that histone modification is essential for normal neural development 76,77 . Several studies have confirmed that specific histone modifications correlate with the onset of NTDs in embryos 27,78–80 .…”