title: ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons.
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.
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Noh
authors.affiliation: 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.
authors.forename: Ian
authors.initials: I
authors.lastname: Maze
authors.affiliation: 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.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Bin
authors.initials: B
authors.lastname: Xiang
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;
authors.forename: Wendy
authors.initials: W
authors.lastname: Wenderski
authors.affiliation: Wisconsin Institute for Discovery, School of Medicine and Public Health, Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53715.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lewis
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065; alliscd@rockefeller.edu lht@tsinghua.edu.cn.
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
mesh_terms: D000818:Animals; D002151:Calorimetry; D047369:Chromatin Immunoprecipitation; D003460:Crystallization; D004265:DNA Helicases / Q000378:metabolism*; D019175:DNA Methylation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004330:Drosophila; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011247:Pregnancy; D012091:Repetitive Sequences, Nucleic Acid / Q000502:physiology*; D000075924:X-linked Nuclear Protein
chemical_list: D017931:DNA Primers; D006657:Histones; D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ATRX; H3K9me3S10ph; crystal structure; heterochromatin; neuron