期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 22, 页码 6820-6827出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1411258112
关键词
ATRX; H3K9me3S10ph; heterochromatin; neuron; crystal structure
资金
- Women & Science Postdoctoral Fellowship
- National Institute of Mental Health [5R01 MH094698-03, P50 MH096890-02]
- Leukemia Lymphoma Society Program Project Award NORTHWESTERN-LLS [7006-13]
- National Natural Science Foundation of China program [31270763]
- Program for New Century Excellent Talents in University
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.
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