Affichage des articles dont le libellé est CHD8. Afficher tous les articles
Affichage des articles dont le libellé est CHD8. Afficher tous les articles

25 mai 2017

Les enzymes de remodelage de la chromatine dépendantes de l'ATP CHD6, CHD7 et CHD8 présentent des activités distinctes de liaison et de remodelage des nucléosomes

Aperçu: G.M.
Une bonne régulation de la chromatine est essentielle à la fonction et à la maintenance du génome. La famille de CHD du groupe III d'enzymes de remodelage de la chromatine dépendantes de l'ATP - comprenant CHD6, CHD7, CHD8 et CHD9 - a des rôles bien documentés dans la régulation de la transcription qui ont un impact sur le développement de l'organisme et l'étiologie de la maladie. Ces quatre enzymes sont similaires dans leurs domaines constitutifs, mais ces enzymes remplissent des rôles étonnamment non redondants dans la cellule, avec des déficiences dans les enzymes individuelles conduisant à des états de maladie dissemblables tels que le syndrome de CHARGE ou les troubles du spectre de l'autisme.
Dans l'ensemble, le travail des chercheurs fournit une base mécanique pour les rôles non redondants et les divers états pathologiques mutants, de ces enzymes in vivo.


J Biol Chem. 2017 May 21. pii: jbc.M117.779470. doi: 10.1074/jbc.M117.779470.

The ATP-dependent Chromatin Remodeling Enzymes CHD6, CHD7, and CHD8 Exhibit Distinct Nucleosome Binding and Remodeling Activities

Author information

1
Dana-Farber Cancer Institute, United States.
2
Dana-Farber Cancer Institute, United States timur_yusufzai@dfci.harvard.edu

Abstract

Proper chromatin regulation is central to genome function and maintenance. The group III CHD family of ATP-dependent chromatin remodeling enzymes--comprising CHD6, CHD7, CHD8, and CHD9--has well-documented roles in transcription regulation impacting both organism development and disease etiology. These four enzymes are similar in their constituent domains, yet these enzymes fill surprisingly non-redundant roles in the cell, with deficiencies in individual enzymes leading to dissimilar disease states such as CHARGE syndrome or autism spectrum disorders. The mechanisms explaining their divergent, non-overlapping functions are unclear. In this study, we performed an in-depth biochemical analysis of purified CHD6, CHD7, and CHD8, and discovered distinct differences in chromatin remodeling specificities and activities among them. We report that CHD6 and CHD7 both bind with high affinity to short linker DNA, while CHD8 requires longer DNA for binding. As a result, CHD8 slides nucleosomes into positions with more flanking linker DNA than does CHD7. Moreover, we found that while CHD7 and CHD8 slide nucleosomes, CHD6 disrupts nucleosomes in a distinct non-sliding manner. The different activities of these enzymes likely lead to differences in chromatin structure, and thereby transcriptional control, at the enhancer and promoter loci where these enzymes bind. Overall, our work provides a mechanistic basis for both the non-redundant roles, and the diverse mutant disease states, of these enzymes in vivo.
PMID: 28533432
DOI: 10.1074/jbc.M117.779470

18 avril 2017

La mutation Chd8 conduit à des comportements autistiques et des circuits striatés détériorés

Aperçu: G.M.
Les chercheurs ont généré des souris mutantes de la lignée germinale avec des mutations de perte de fonction dans Chd8, une mutation de novo fortement associée aux TSA, et isl démontrent que ces souris présentent des comportements caractéristiques du TSA, une macrocéphalie et des anomalies craniofaciales similaires aux phénotypes des personnes avec un diagnostic de TSA.
Les souris Chd8 +/- présentent une large dérégulation spécifique de la région du cerveau des principaux processus de régulation et cellulaires, notamment la modification des histones et de la chromatine, le traitement des ARNm et des protéines, la signalisation Wnt et la régulation du cycle cellulaire, ainsi qu'une physiologie synaptique altérée dans les neurones épineux moyens du noyau accumbens. La perturbation du Chd8 chez les souris adultes récapitule l'amélioration du comportement d'apprentissage moteur acquis chez les animaux Chd8 +/-, ce qui suggère un rôle pour la CHD8 dans les circuits du stratum des adultes.  
Ces résultats supportent un mécanisme reliant la modification de la chromatine au dysfonctionnement striatal et la pathologie moléculaire des TSA. 


Cell Rep. 2017 Apr 11;19(2):335-350. doi: 10.1016/j.celrep.2017.03.052.

Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits

Author information

1
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biosystems Science and Engineering, ETH Zurich, Basel 4058, Switzerland; Department of Chemistry, University of Basel, Basel 4056, Switzerland. Electronic address: rplatt@ethz.ch
2
Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA.
3
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA.
4
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
5
Department of Biosystems Science and Engineering, ETH Zurich, Basel 4058, Switzerland.
6
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Radiology, Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
7
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
8
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
9
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
10
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: zhang@broadinstitute.org

Abstract

Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We generated germline mutant mice with loss-of-function mutations in Chd8, a de novo mutation strongly associated with ASD, and demonstrate that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8+/- mice display a broad, brain-region-specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell-cycle regulation. We also find altered synaptic physiology in medium spiny neurons of the nucleus accumbens. Perturbation of Chd8 in adult mice recapitulates improved acquired motor learning behavior found in Chd8+/- animals, suggesting a role for CHD8 in adult striatal circuits. These results support a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.
PMID: 28402856
DOI: 10.1016/j.celrep.2017.03.052

10 octobre 2014

CHD8 régule les voies du développement neurologique associées à un trouble du spectre autistique dans les progéniteurs neuronaux.

Traduction: G.M.

Proc Natl Acad Sci U S A. 2014 Oct 7. pii: 201405266. [Epub ahead of print]

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors

Author information

  • 1Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Neurology and.
  • 2Molecular Neurogenetics Unit and Departments of Neurology and.
  • 3Center for Human Disease Modeling and.
  • 4Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114;
  • 5Molecular Neurogenetics Unit and.
  • 6Departments of Pediatrics, Medical Genetics, and Pathology, The Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri Hospitals and Clinics, Columbia, MO 65201;
  • 7Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139; and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142.
  • 8Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Neurology and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142.
  • 9Center for Human Disease Modeling and Department of Cell Biology, Duke University, Durham, NC 27710;
  • 10Molecular Neurogenetics Unit and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142 Genetics, Harvard Medical School, Boston, MA 02115;
  • 11Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Neurology and Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142 talkowski@chgr.mgh.harvard.edu.

Abstract

Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. 
Les mutations tronquées de la chromodomaine hélicase DNA-binding protéine 8 (CHD8), et de nombreux autres gènes avec des fonctions diverses, sont des facteurs à fort effet de risque de troubles du spectre autistique (TSA), suggérant de multiples mécanismes de la pathogenèse.
We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10-8) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10-10). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations.
These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.
Ces données indiquent que la perturbation hétérozygote de CHD8 précipite un réseau de changements d'expression des gènes impliqués dans les voies du développement neurologique dans laquelle de nombreux gènes associés au TSA peuvent converger sur les mécanismes communs de la pathogenèse

PMID: 25294932