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Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):6820-7. doi: 10.1073/pnas.1411258112. Epub 2014 Dec 23.

ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons.

Author information

1
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;
2
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029; alliscd@rockefeller.edu lht@tsinghua.edu.cn.
3
College of Life Sciences, Peking University, Beijing 100871, People's Republic of China; Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China; and.
4
Wisconsin Institute for Discovery, School of Medicine and Public Health, Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53715.
5
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
6
Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China; and alliscd@rockefeller.edu lht@tsinghua.edu.cn.
7
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065; alliscd@rockefeller.edu lht@tsinghua.edu.cn.

Abstract

ATRX (the alpha thalassemia/mental retardation syndrome X-linked protein) is a member of the switch2/sucrose nonfermentable2 (SWI2/SNF2) family of chromatin-remodeling proteins and primarily functions at heterochromatic loci via its recognition of "repressive" histone modifications [e.g., histone H3 lysine 9 tri-methylation (H3K9me3)]. Despite significant roles for ATRX during normal neural development, as well as its relationship to human disease, ATRX function in the central nervous system is not well understood. Here, we describe ATRX's ability to recognize an activity-dependent combinatorial histone modification, histone H3 lysine 9 tri-methylation/serine 10 phosphorylation (H3K9me3S10ph), in postmitotic neurons. In neurons, this "methyl/phos" switch occurs exclusively after periods of stimulation and is highly enriched at heterochromatic repeats associated with centromeres. Using a multifaceted approach, we reveal that H3K9me3S10ph-bound Atrx represses noncoding transcription of centromeric minor satellite sequences during instances of heightened activity. Our results indicate an essential interaction between ATRX and a previously uncharacterized histone modification in the central nervous system and suggest a potential role for abnormal repetitive element transcription in pathological states manifested by ATRX dysfunction.

KEYWORDS:

ATRX; H3K9me3S10ph; crystal structure; heterochromatin; neuron

PMID:
25538301
PMCID:
PMC4460490
DOI:
10.1073/pnas.1411258112
[Indexed for MEDLINE]
Free PMC Article

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