Abstract
Posttranslational modification of histones and related gene regulation are shown to be affected in an increasing number of neurological disorders. SETD1A is a chromatin remodeler that influences gene expression through the modulation of mono- di- and trimethylation marks on Histone-H3-Lysine-4 (H3K4me1/2/3). H3K4 methylation is predominantly described to result in transcriptional activation, with its mono- di- and trimethylated forms differentially enriched at promoters or enhancers. Recently, dominant mostly de novo variants in SETD1A have clinically been linked to developmental delay, intellectual disability (DD/ID), and schizophrenia (SCZ). Affected individuals often display both developmental and neuropsychiatric abnormalities. The primary diagnoses are mainly dependent on the age at which the individual is assessed. Investigations in mouse models of SETD1A dysfunction have been able to recapitulate key behavioral features associated with ID and SCZ. Furthermore, functional investigations suggest disrupted synaptic and neuronal network function in these mouse models. In this review, we provide an overview of pre-clinical studies on the role of SETD1A in neuronal development. A better understanding of the pathobiology underlying these disorders may provide novel opportunities for therapeutic intervention. As such, we will discuss possible strategies to move forward in elucidating the genotype-phenotype correlation in SETD1A associated disorders.
Highlights
Chromatin modification and the related regulation of gene expression patterns have been linked to several neurological disorders, in particular neurodevelopmental (NDD) or neuropsychiatric disorders (NPD; Gabriele et al, 2018; Satterstrom et al, 2020; Mossink et al, 2021)
The basic building block for chromatin is the nucleosome, which consists of a 147 base pair DNA structure that wraps around an octamer of the four core histones H3, H4, H2A, and H2B
H3K4me1, 2, and 3 localizes to specific parts of the nucleosome: H3K4me1 is distributed at enhancer regions, H3K4me2 is found in nucleosomes further downstream in the body of genes, and H3K4me3 is located in nucleosomes near the transcription start sites (TSS) of expressed genes, presumably at promoter regions (Kusch, 2012)
Summary
H3K4 Methylation and Its Role in Neurodevelopmental and Neuropsychiatric Disorders. Posttranslational modification of histones and related gene regulation are shown to be affected in an increasing number of neurological disorders. SETD1A is a chromatin remodeler that influences gene expression through the modulation of mono- di- and trimethylation marks on Histone-H3-Lysine-4 (H3K4me1/2/3). Dominant mostly de novo variants in SETD1A have clinically been linked to developmental delay, intellectual disability (DD/ID), and schizophrenia (SCZ). Affected individuals often display both developmental and neuropsychiatric abnormalities. Investigations in mouse models of SETD1A dysfunction have been able to recapitulate key behavioral features associated with ID and SCZ. We provide an overview of pre-clinical studies on the role of SETD1A in neuronal development. We will discuss possible strategies to move forward in elucidating the genotype-phenotype correlation in SETD1A associated disorders
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