Kernohan Kristin D, Vernimmen Douglas, Gloor Gregory B, Bérubé Nathalie G
Department of Biochemistry, University of Western Ontario, London N6C 2V5, Canada Children's Health Research Institute, London, Canada.
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Nucleic Acids Res. 2014 Jul;42(13):8356-68. doi: 10.1093/nar/gku564. Epub 2014 Jul 2.
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.
ATRX和MeCP2属于一类不断扩大的与染色质相关的蛋白质，这些蛋白质与人类神经发育障碍有关，尽管它们的基因调控活性尚未完全明确。ATRX的缺失会阻止出生后脑内印记基因网络的完全抑制，在本研究中，我们探讨了这种调控的机制。我们发现，ATRX分别与许多印记结构域结合，但神经元细胞核中印记结构域之间的短暂共定位并不需要ATRX。我们证明，MeCP2是ATRX招募所必需的，并且ATRX或MeCP2的缺陷会导致与CTCF结合位点处核小体密度改变相关的长程染色质相互作用频率降低以及CTCF占有率降低。这些发现表明，MeCP2和ATRX通过维持有利于CTCF结合和高阶染色质结构维持的核小体构型，在一部分印记结构域调控基因表达。
