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Benjamin J Patty, Sarah J Hainer
Nucleosome remodeling complexes and other regulatory factors work in concert to build a chromatin environment that directs the expression of a distinct set of genes in each cell using cis-regulatory elements (CREs), such as promoters and enhancers, that drive transcription of both mRNAs and CRE-associated non-coding RNAs (ncRNAs). Two classes of CRE-associated ncRNAs include upstream antisense RNAs (uaRNAs), which are transcribed divergently from a shared mRNA promoter, and enhancer RNAs (eRNAs), which are transcribed bidirectionally from active enhancers...
April 15, 2024: bioRxiv
#2
JOURNAL ARTICLE
Emily Neuhaus, Hannah Rea, Elizabeth Jones, Hannah Benavidez, Conor Miles, Alana Whiting, Margaret Johansson, Curtis Eayrs, Evangeline C Kurtz-Nelson, Rachel Earl, Raphael A Bernier, Evan E Eichler
BACKGROUND: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice...
April 15, 2024: Journal of Neurodevelopmental Disorders
#3
JOURNAL ARTICLE
Manal Tabbaa, Pat Levitt
Mutations in CHD8 are one of the highest genetic risk factors for autism spectrum disorder. Studies in mice that investigate underlying mechanisms have shown Chd8 haploinsufficient mice display some trait disruptions that mimic clinical phenotypes, although inconsistencies have been reported in some traits across different models on the same strain background. One source of variation across studies may be the impact of Chd8 haploinsufficiency on maternal-offspring interactions. While differences in maternal care as a function of Chd8 genotype have not been studied directly, a previous study showed that pup survival was reduced when reared by Chd8 heterozygous dams compared with wild-type (WT) dams, suggesting altered maternal care as a function of Chd8 genotype...
April 2024: Genes, Brain, and Behavior
#4
George T Chen, Gayatri Nair, Aubrey J Osorio, Sandra M Holley, Kimiya Ghassemzadeh, Jose Gonzalez, Congyi Lu, Neville E Sanjana, Carlos Cepeda, Daniel H Geschwind
Autism Spectrum Disorder (ASD) is a highly heritable condition with diverse clinical presentations. Approximately 20% of ASD's genetic susceptibility is imparted by de novo mutations of major effect, most of which cause haploinsufficiency. We mapped enhancers of two high confidence autism genes - CHD8 and SCN2A and used CRISPR-based gene activation (CRISPR-A) in hPSC-derived excitatory neurons and cerebral forebrain organoids to correct the effects of haploinsufficiency, taking advantage of the presence of a wildtype allele of each gene and endogenous gene regulation...
March 14, 2024: bioRxiv
#5
JOURNAL ARTICLE
Robert A Ellingford, Mizuki Tojo, M Albert Basson, Laura C Andreae
CHD8 is a high penetrance, high confidence risk gene for autism spectrum disorder (ASD), a neurodevelopmental disorder that is substantially more prevalent among males than among females. Recent studies have demonstrated variable sex differences in the behaviors and synaptic phenotypes of mice carrying different heterozygous ASD-associated mutations in Chd8 . We examined functional and structural cellular phenotypes linked to synaptic transmission in deep layer pyramidal neurons of the prefrontal cortex in male and female mice carrying a heterozygous, loss-of-function Chd8 mutation in the C57BL/6J strain across development from postnatal day 2 to adulthood...
April 1, 2024: ACS Chemical Neuroscience
#6
JOURNAL ARTICLE
Emily L Hendricks, Faith L W Liebl
Chromodomain helicase DNA binding domain (CHD) proteins, including CHD7 and CHD8, remodel chromatin to enable transcriptional programs. Both proteins are important for proper neural development as heterozygous mutations in Chd7 and Chd8 are causative for CHARGE syndrome and correlated with autism spectrum disorders, respectively. Their roles in mature neurons are poorly understood despite influencing the expression of genes required for cell adhesion, neurotransmission, and synaptic plasticity. The Drosophila homolog of CHD7 and CHD8, Kismet (Kis), promotes neurotransmission, endocytosis, and larval locomotion...
2024: PloS One
#7
JOURNAL ARTICLE
Ireland R Smith, Emily L Hendricks, Nina K Latcheva, Daniel R Marenda, Faith L W Liebl
The appropriate expression and localization of cell surface cell adhesion molecules must be tightly regulated for optimal synaptic growth and function. How neuronal plasma membrane proteins, including cell adhesion molecules, cycle between early endosomes and the plasma membrane is poorly understood. Here we show that the Drosophila homolog of the chromatin remodeling enzymes CHD7 and CHD8, Kismet, represses the synaptic levels of several cell adhesion molecules. Neuroligins 1 and 3 and the integrins αPS2 and βPS are increased at kismet mutant synapses but Kismet only directly regulates transcription of neuroligin 2 ...
March 6, 2024: International Journal of Molecular Sciences
#8
JOURNAL ARTICLE
Ugo Sorrentino, Sylvia Boesch, Diane Doummar, Claudia Ravelli, Tereza Serranova, Elisabetta Indelicato, Juliane Winkelmann, Lydie Burglen, Robert Jech, Michael Zech
BACKGROUND: Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems...
March 5, 2024: Journal of Neurology
#9
JOURNAL ARTICLE
Taichi Shiraishi, Yuta Katayama, Masaaki Nishiyama, Hirotaka Shoji, Tsuyoshi Miyakawa, Taisuke Mizoo, Akinobu Matsumoto, Atsushi Hijikata, Tsuyoshi Shirai, Kouta Mayanagi, Keiichi I Nakayama
CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior...
March 5, 2024: Molecular Psychiatry
#10
JOURNAL ARTICLE
Kyung Eun Paik, GenaLynne C Mooneyham
BACKGROUND: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder. Unique ASD subtypes have been proposed based on specific genotype-phenotype combinations. The ASD subtype associated with various chromodomain helicase DNA-binding protein 8 (CHD8) mutations has been associated with an incidence of autistic regression greater than that of all-cause ASD, but the mean age of onset of this subtype remains unknown. METHODS: Here we describe a patient with a known de novo CHD8 gene mutation (heterozygous c...
January 5, 2024: Pediatric Neurology
#11
JOURNAL ARTICLE
Katerina Gregorova, Lukas Plachy, Petra Dusatkova, Klara Maratova, Vit Neuman, Stanislava Kolouskova, Marta Snajderova, Barbora Obermannova, Lenka Drnkova, Ondrej Soucek, Jan Lebl, Zdenek Sumnik, Stepanka Pruhova
CONTEXT: Familial tall stature (FTS) is considered to be a benign variant of growth with a presumed polygenic etiology. However, monogenic disorders with possible associated pathological features could also be hidden under the FTS phenotype. OBJECTIVES: To elucidate the genetic etiology in families with FTS and to describe their phenotype in detail. DESIGN, SETTINGS AND PATIENTS: Children with FTS (height in both the child and his/her taller parent >2 SD) referred to the Endocrinology center of Motol University Hospital were enrolled to the study...
February 2, 2024: Journal of Clinical Endocrinology and Metabolism
#12
JOURNAL ARTICLE
M Albert Basson
Heterozygous, de novo, loss-of-function variants of the CHD8 gene are associated with a high penetrance of autism and other neurodevelopmental phenotypes. Identifying the neurodevelopmental functions of high-confidence autism risk genes like CHD8 may improve our understanding of the neurodevelopmental mechanisms that underlie autism spectrum disorders. Over the last decade, a complex picture of pleiotropic CHD8 functions and mechanisms of action has emerged. Multiple brain and non-brain cell types and progenitors appear to be affected by CHD8 haploinsufficiency...
January 30, 2024: Biochemical Society Transactions
#13
JOURNAL ARTICLE
Chromatin remodeler CHD8 is required for spermatogonial proliferation and early meiotic progression.
Kenta Nitahara, Atsuki Kawamura, Yuka Kitamura, Kiyoko Kato, Satoshi H Namekawa, Masaaki Nishiyama
Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia and the failure of meiotic double-strand break (DSB) formation, leading to meiotic prophase I arrest and cell death...
January 16, 2024: Nucleic Acids Research
#14
JOURNAL ARTICLE
Kinji Ohno
Congenital myasthenic syndromes (CMS) are characterized by congenital defects in the neuromuscular signal transmission and are caused by pathogenic variants in 36 genes. Recently identified forms of CMS include TOR1AIP1-CMS, CHD8-CMS, PURA-CMS, and TEFM-CMS. Most forms of CMS are caused by autosomal recessive variants, whereas four forms of CMS are caused by autosomal dominant variants, in which adult-onset cases are not rare. As myasthenic features are not always observed and muscle hypotrophy is sometimes observed, CMS should be considered in differential diagnosis of congenital myopathies and other neuromuscular diseases...
January 2024: Brain and Nerve, Shinkei Kenkyū No Shinpo
#15
REVIEW
Andrea Cerase, Philip Avner
The chromodomain helicase DNA-binding protein 8 (CHD8) is a chromatin remodeler whose mutation is associated, with high penetrance, with autism. Individuals with CHD8 mutations share common symptoms such as autistic behaviour, cognitive impairment, schizophrenia comorbidity, and phenotypic features such as macrocephaly and facial defects. Chd8 -deficient mouse models recapitulate most of the phenotypes seen in the brain and other organs of humans. It is known that CHD8 regulates - directly and indirectly - neuronal, autism spectrum disorder (ASDs)-associated genes and long non-coding RNAs (lncRNAs) genes, which, in turn, regulate fundamental aspects of neuronal differentiation and brain development and function...
2023: Current research in neurobiology
#16
JOURNAL ARTICLE
Megan E Rowland, Yan Jiang, Sarfraz Shafiq, Alireza Ghahramani, Miguel A Pena-Ortiz, Vanessa Dumeaux, Nathalie G Bérubé
Myelin, an extension of the oligodendrocyte plasma membrane, wraps around axons to facilitate nerve conduction. Myelination is compromised in ATR-X intellectual disability syndrome patients, but the causes are unknown. We show that loss of ATRX leads to myelination deficits in male mice that are partially rectified upon systemic thyroxine administration. Targeted ATRX inactivation in either neurons or oligodendrocyte progenitor cells (OPCs) reveals OPC-intrinsic effects on myelination. OPCs lacking ATRX fail to differentiate along the oligodendrocyte lineage and acquire a more plastic state that favors astrocytic differentiation in vitro and in vivo...
November 4, 2023: Nature Communications
#17
Jianyu Yang, Kuangyu Yen, Shaun Mahony
Genome-wide nucleosome profiles are predominantly characterized using MNase-seq, which involves extensive MNase digestion and size selection to enrich for mono-nucleosome-sized fragments. Most available MNase-seq analysis packages assume that nucleosomes uniformly protect 147bp DNA fragments. However, some nucleosomes with atypical histone or chemical compositions protect shorter lengths of DNA. The rigid assumptions imposed by current nucleosome analysis packages ignore variation in nucleosome lengths, potentially blinding investigators to regulatory roles played by atypical nucleosomes...
October 20, 2023: bioRxiv
#18
JOURNAL ARTICLE
Thomas Husson, François Lecoquierre, Gaël Nicolas, Anne-Claire Richard, Alexandra Afenjar, Séverine Audebert-Bellanger, Catherine Badens, Frédéric Bilan, Varoona Bizaoui, Anne Boland, Marie-Noëlle Bonnet-Dupeyron, Elise Brischoux-Boucher, Céline Bonnet, Marie Bournez, Odile Boute, Perrine Brunelle, Roseline Caumes, Perrine Charles, Nicolas Chassaing, Nicolas Chatron, Benjamin Cogné, Estelle Colin, Valérie Cormier-Daire, Rodolphe Dard, Benjamin Dauriat, Julian Delanne, Jean-François Deleuze, Florence Demurger, Anne-Sophie Denommé-Pichon, Christel Depienne, Anne Dieux, Christèle Dubourg, Patrick Edery, Salima El Chehadeh, Laurence Faivre, Patricia Fergelot, Mélanie Fradin, Aurore Garde, David Geneviève, Brigitte Gilbert-Dussardier, Cyril Goizet, Alice Goldenberg, Evan Gouy, Anne-Marie Guerrot, Anne Guimier, Inès Harzalla, Delphine Héron, Bertrand Isidor, Didier Lacombe, Xavier Le Guillou Horn, Boris Keren, Alma Kuechler, Elodie Lacaze, Alinoë Lavillaureix, Daphné Lehalle, Gaëtan Lesca, James Lespinasse, Jonathan Levy, Stanislas Lyonnet, Godeliève Morel, Nolwenn Jean-Marçais, Sandrine Marlin, Luisa Marsili, Cyril Mignot, Sophie Nambot, Mathilde Nizon, Robert Olaso, Laurent Pasquier, Laurine Perrin, Florence Petit, Veronique Pingault, Amélie Piton, Fabienne Prieur, Audrey Putoux, Marc Planes, Sylvie Odent, Chloé Quélin, Sylvia Quemener-Redon, Mélanie Rama, Marlène Rio, Massimiliano Rossi, Elise Schaefer, Sophie Rondeau, Pascale Saugier-Veber, Thomas Smol, Sabine Sigaudy, Renaud Touraine, Frederic Tran Mau-Them, Aurélien Trimouille, Julien Van Gils, Clémence Vanlerberghe, Valérie Vantalon, Gabriella Vera, Marie Vincent, Alban Ziegler, Olivier Guillin, Dominique Campion, Camille Charbonnier
Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 101 carriers of (likely) pathogenic variants in ten different genes, 57 VUS carriers, and 25 healthy controls...
October 23, 2023: European Journal of Human Genetics: EJHG
#19
Maider Astorkia, Yang Liu, Erika M Pedrosa, Herbert M Lachman, Deyou Zheng
About 100 genes have been associated with significantly increased risks of autism spectrum disorders (ASD) with an estimate of ∼1000 genes that may be involved. The new challenge now is to investigate the molecular and cellular functions of these genes during neural and brain development, and then even more challenging, to link the altered molecular and cellular phenotypes to the ASD clinical manifestations. In this study, we use single cell RNA-seq analysis to study one of the top risk gene, CHD8 , in cerebral organoids, which models early neural development...
September 27, 2023: bioRxiv
#20
JOURNAL ARTICLE
Xi Shi, Congyi Lu, Alba Corman, Alexandra Nikish, Yang Zhou, Randy J Platt, Ivan Iossifov, Feng Zhang, Jen Q Pan, Neville E Sanjana
Whole-exome sequencing of autism spectrum disorder (ASD) probands and unaffected family members has identified many genes harboring de novo variants suspected to play a causal role in the disorder. Of these, chromodomain helicase DNA-binding protein 8 (CHD8) is the most recurrently mutated. Despite the prevalence of CHD8 mutations, we have little insight into how CHD8 loss affects genome organization or the functional consequences of these molecular alterations in neurons. Here, we engineered two isogenic human embryonic stem cell lines with CHD8 loss-of-function mutations and characterized differences in differentiated human cortical neurons...
October 5, 2023: American Journal of Human Genetics
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