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Chromatin Remodeler CHD8 in Autism and Brain Development

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Chromatin Remodeler CHD8 in Autism and Brain Development Journal of Clinical Medicine Review Chromatin Remodeler CHD8 in Autism and Brain Development Anke Hoffmann and Dietmar Spengler * Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, 80804 Munich, Germany; [email protected] * Correspondence: [email protected] Abstract: Chromodomain Helicase DNA-binding 8 (CHD8) is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental syndrome with the core symptoms of autism, macrocephaly, and facial dysmorphism. The role of CHD8 is well-characterized at the structural, biochemical, and transcriptional level. By contrast, much less is understood regarding how mutations in CHD8 underpin altered brain function and mental disease. Studies on various model organisms have been proven critical to tackle this challenge. Here, we scrutinize recent advances in this field with a focus on phenotypes in transgenic animal models and highlight key findings on neurodevelopment, neuronal connectivity, neurotransmission, synaptic and homeostatic plasticity, and habituation. Against this backdrop, we further discuss how to improve future animal studies, both in terms of technical issues and with respect to the sex- specific effects of Chd8 mutations for neuronal and higher-systems level function. We also consider outstanding questions in the field including ‘humanized’ mice models, therapeutic interventions, and how the use of pluripotent stem cell-derived cerebral organoids might help to address differences in neurodevelopment trajectories between model organisms and humans. Keywords: autism; neurodevelopmental disorders; chromatin regulation; neurodevelopment; neu- ronal connectivity; neurotransmission; neuronal plasticity; pluripotent stem cells Citation: Hoffmann, A.; Spengler, D. Chromatin Remodeler CHD8 in Autism and Brain Development. J. 1. Introduction Clin. Med. 2021 10 , , 366. https:// The nuclear DNA of eukaryotic cells is tightly packaged with the help of histone doi.org/10.3390/jcm10020366 proteins to form the so-called chromatin. This structure can adopt an open (transcrip- tionally active) or closed (transcriptionally inactive) configuration that critically controls Received: 8 December 2020 the access of transcription factors (TFs) to their binding sites. Epigenetic factors control Accepted: 14 January 2021 Published: 19 January 2021 these chromatin states by imposing posttranslational modifications of free histone tails and by chromatin remodeling (reviewed in [1]). Chromatin states additionally depend on Publisher’s Note: MDPI stays neutral epigenetic factors imposing DNA modifications (e.g., DNA methylation) (reviewed in [2]). with regard to jurisdictional claims in Both processes, modification of chromatin and of DNA, closely interact with each other and published maps and institutional affil- play an important role in the precise temporal and spatial control of gene expression during iations. development and beyond. Consistent with this scenario, epigenetic factors have been increasingly recognized for their role in the initiation and progression of mental diseases (reviewed in [3,4]). Mutations in genes that encode for chromatin remodelers (CRs) have been origi- nally identified as the genetic cause of distinct neurodevelopmental syndromes (reviewed Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. in [5,6]). In addition, genome-wide association studies (GWAS) on neurodevelopmental This article is an open access article disorders, including intellectual disability (ID) and ASD, have reported genetic variation in distributed under the terms and CRs to be significantly associated with disease. These findings have spurred research on conditions of the Creative Commons the biochemical, structural, and biological properties of CRs. Attribution (CC BY) license (https:// In this review, we discuss recent progress on the role of CHD8 in autism and neurode- creativecommons.org/licenses/by/ velopment. To prepare this discussion, we firstly summarize key findings on the structural 4.0/). and biochemical features of CHD8 as well as its relationship to other members of the CHD J. Clin. Med. 2021, 10, 366. https://doi.org/10.3390/jcm10020366 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 9, x FOR PEER REVIEW 2 of 23 In this review, we discuss recent progress on the role of CHD8 in autism and neurodevelopment. To prepare this discussion, we firstly summarize key findings on the J. Clin. Med. 2021, 10, 366 structural and biochemical features of CHD8 as well as its relationship to other members2 of 23 of the CHD family. Following this, we reconsider present evidence for CHD8 as a high confidence risk factor for ASD and as a genetic cause of a distinct neurodevelopmental family. Following this, we reconsider present evidence for CHD8 as a high confidence risk syndrome highly associated with autism. Against this backdrop, we move on to examine factor for ASD and as a genetic cause of a distinct neurodevelopmental syndrome highly associatedthe question with of autism.how various Against model this organisms backdrop, we have move helped on to to examine advance the our question insight into of how the variousbiological model role organisms of Chd8 in have the helpeddeveloping to advance and mature our insight brain. into We the focus biological on the role phenotypic of Chd8 ineffects the developing of Chd8 andmutations mature and brain. discuss We focus transcriptional on the phenotypic changes effects in ofrelationChd8 mutations to these andphenotypes. discuss transcriptional Readers interested changes in in the relation broader to these transcriptional phenotypes. function Readers of interested CHD8 are in thereferred broader to transcriptional previous reviews function [7,8]. of CHD8Finally,are referredwe consider to previous continuing reviews challenges [7,8]. Finally, for wetranslational consider continuing animal studies challenges and how for pluripotent translational stem animal cell‐derived studies models and how could pluripotent advance steminsight cell-derived into the role models of CHD8 could in advance autism. insight into the role of CHD8 in autism. 2.2. CHD8CHD8 IsIs aa MemberMember of of the the CHD CHD Family Family of of CRs CRs TheThe nucleosome nucleosome is is the the basic basic subunit subunit of of chromatin chromatin and and consists consists of of a a segment segment of of DNA DNA woundwound around around eight eight histone histone proteins proteins known known as histone as octamer.histone CRsoctamer. regulate CRs nucleosome regulate sliding,nucleosome conformational sliding, conformational changes of nucleosomal changes of DNA, nucleosomal and exchange DNA, of and histone exchange variants of (reviewedhistone variants in [9]). All(reviewed of these processesin [9]). All influence of these chromatin processes configuration, influence andchromatin conse- quently,configuration, gene expression. and consequently, Based on gene their expression. biochemical Based activities, on their CRs biochemical are distinguished activities, in thoseCRs are regulating distinguished post-translational in those regulating modification post‐translational of free histone modification tails and in of those free regulat- histone ingtails histone-DNA and in those contact regulating within histone the nucleosome‐DNA contact through within ATP the nucleosome (adenosine triphosphate) through ATP hydrolysis.(adenosine triphosphate) hydrolysis. TheThe catalytic catalytic ATPase ATPase domain domain is is conserved conserved among among CR CR families families (including (including SWI/SNF SWI/SNF (switch/sucrose-non-fermenting),(switch/sucrose‐non‐fermenting), ISWIISWI (imitation(imitation switch),switch), andand INO80INO80 (inositol (inositol requiring requiring 80)80) andand CHD),CHD), andand usesuses ATPATP to to promote promote translocation translocation downdown thethe DNADNA minor minor groove groove (reviewed(reviewed inin [10[10]).]). AdditionalAdditional domains next toto thethe ATPaseATPase domaindomain areare importantimportant toto chromatinchromatin binding,binding, interaction interaction with with specific specific histone histone modifications, modifications, and/or and/or regulation regulation of of ATPaseATPase activity activity [ 9[9].]. ForFor example, example, CHDs CHDs contain contain an an N-terminal N‐terminal tandem tandem chromodomain chromodomain mediatingmediating binding binding to to methylated methylated lysine lysine residues residues in in free free histone histone tails tails (Figure (Figure1 ).1). FigureFigure 1. 1.Schematic Schematic representation representation of of the the mammalian mammalian CHD CHD family family with with conserved conserved domains domains shown for eachshown subfamily. for each The subfamily. signature The motif signature of the entire motif CHD of the family entire is CHD an N-terminal family is an tandem N‐terminal chromodomain tandem (greenchromodomain boxes) responsible (green boxes) for chromatin responsible binding. for chromatin The central binding. SNF2-family The central ATPase SNF2 domain‐family consistsATPase ofdomain two lobes consists (orange of two boxes) lobes with (orange each boxes) containing with 2each tandem containing RecA-like 2 tandem folds RecA parts‐ knownlike folds as parts DExx andknown HELIC. as DExx The ATPaseand HELIC. domain The uses ATPase ATP domain hydrolysis uses to ATP guide hydrolysis toward translocation to guide toward down the DNA translocation down the DNA minor groove. CHD1 and
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