ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons
ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons
复制标题
ATRX 可耐受活性依赖性组蛋白 H3 甲基/磷酸转换，以维持神经元中重复元件的沉默
DOI：
10.1073/pnas.1411258112
复制
发表时间：
2015-06-02
影响因子：
11.1
通讯作者：
Allis, C. David
中科院分区：
文献类型：
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作者：
Noh, Kyung-Min;Maze, Ian;Allis, C. David
ATRX（α地中海贫血/精神发育迟滞综合征 X 连锁蛋白）是染色质重塑蛋白 switch2/蔗糖不可发酵 2 (SWI2/SNF2) 家族的成员，主要通过识别“抑制性”组蛋白修饰 [例如组蛋白 H3 赖氨酸 9 三甲基化 (H3K9me3)] 在异染色质位点发挥作用。尽管 ATRX 在正常神经发育及其与人类疾病的关系中发挥着重要作用，但 ATRX 在中枢神经系统中的功能尚不清楚。在这里，我们描述了 ATRX 在有丝分裂后神经元中识别活性依赖性组合组蛋白修饰、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”转换仅在刺激期后发生，并且在与着丝粒相关的异染色质重复序列中高度富集。使用多方面的方法，我们揭示了 H3K9me3S10ph 结合的 Atrx 在活性增强的情况下抑制着丝粒小卫星序列的非编码转录。我们的结果表明 ATRX 与中枢神经系统中先前未表征的组蛋白修饰之间存在重要的相互作用，并表明异常重复元件转录在 ATRX 功能障碍所表现的病理状态中具有潜在作用。
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.