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Nucleic Acids Res. 2014 Jul;42(13):8356-68. doi: 10.1093/nar/gku564. Epub 2014 Jul 2.

Analysis of neonatal brain lacking ATRX or MeCP2 reveals changes in nucleosome density, CTCF binding and chromatin looping.

Author information

1
Department of Biochemistry, University of Western Ontario, London N6C 2V5, Canada Children's Health Research Institute, London, Canada.
2
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
3
Department of Biochemistry, University of Western Ontario, London N6C 2V5, Canada.
4
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.

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.

PMID:
24990380
PMCID:
PMC4117782
DOI:
10.1093/nar/gku564
[Indexed for MEDLINE]
Free PMC Article

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