title: Analysis of neonatal brain lacking ATRX or MeCP2 reveals changes in nucleosome density, CTCF binding and chromatin looping.
abstract: ATRX and MeCP2 belong to an expanding group of chromatin-associated proteins implicated in human neurodevelopmental disorders, although their gene-regulatory activities are not fully resolved. Loss of ATRX prevents full repression of an imprinted gene network in the postnatal brain and in this study we address the mechanistic aspects of this regulation. We show that ATRX binds many imprinted domains individually but that transient co-localization between imprinted domains in the nuclei of neurons does not require ATRX. We demonstrate that MeCP2 is required for ATRX recruitment and that deficiency of either ATRX or MeCP2 causes decreased frequency of long-range chromatin interactions associated with altered nucleosome density at CTCF-binding sites and reduced CTCF occupancy. These findings indicate that MeCP2 and ATRX regulate gene expression at a subset of imprinted domains by maintaining a nucleosome configuration conducive to CTCF binding and to the maintenance of higher order chromatin structure.
authors.affiliation: Department of Biochemistry, University of Western Ontario, London N6C 2V5, Canada Children's Health Research Institute, London, Canada.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Kernohan
authors.affiliation: Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Douglas
authors.initials: D
authors.lastname: Vernimmen
authors.affiliation: Department of Biochemistry, University of Western Ontario, London N6C 2V5, Canada.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Gloor
authors.affiliation: Department of Biochemistry, University of Western Ontario, London N6C 2V5, Canada Children's Health Research Institute, London, Canada Department of Paediatrics, University of Western Ontario, London N6C 2V5, Canada nberube@uwo.ca.
authors.forename: Nathalie G
authors.initials: NG
authors.lastname: Bérubé
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D000076246:CCCTC-Binding Factor; D002135:Calcium-Binding Proteins; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017353:Gene Deletion; D018392:Genomic Imprinting; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009707:Nucleosomes / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D000075924:X-linked Nuclear Protein
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002135:Calcium-Binding Proteins; D002843:Chromatin; C000619698:Ctcf protein, mouse; C512925:Dlk1 protein, mouse; C094335:H19 long non-coding RNA; D036341:Intercellular Signaling Peptides and Proteins; C422882:MEG3 non-coding RNA, mouse; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009687:Nuclear Proteins; D009707:Nucleosomes; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D007335:Insulin-Like Growth Factor II; D004265:DNA Helicases; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein