Noh Kyung-Min, Maze Ian, Zhao Dan, Xiang Bin, Wenderski Wendy, Lewis Peter W, Shen Li, Li Haitao, Allis C David
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;
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;
Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):6820-7. doi: 10.1073/pnas.1411258112. Epub 2014 Dec 23.
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.
ATRX（α地中海贫血/智力发育迟缓综合征X连锁蛋白）是染色质重塑蛋白的switch2/蔗糖非发酵2（SWI2/SNF2）家族成员，主要通过识别“抑制性”组蛋白修饰[如组蛋白H3赖氨酸9三甲基化（H3K9me3）]在异染色质位点发挥作用。尽管ATRX在正常神经发育过程中发挥着重要作用，且与人类疾病相关，但其在中枢神经系统中的功能仍未得到充分了解。在此，我们描述了ATRX在有丝分裂后神经元中识别一种活性依赖的组合组蛋白修饰——组蛋白H3赖氨酸9三甲基化/丝氨酸10磷酸化（H3K9me3S10ph）的能力。在神经元中，这种“甲基/磷酸”开关仅在刺激期后出现，且在与着丝粒相关的异染色质重复序列中高度富集。通过多方面的研究方法，我们发现与H3K9me3S10ph结合的Atrx在活性增强时会抑制着丝粒小卫星序列的非编码转录。我们的结果表明ATRX与中枢神经系统中一种先前未被表征的组蛋白修饰之间存在重要相互作用，并提示异常重复元件转录在ATRX功能障碍所表现的病理状态中可能发挥的作用。
