ATRX, a member of the SNF2 family of helicase/ATPases, is required for chromosome alignment and meiotic spindle organization in metaphase II stage mouse oocytes
ATRX, a member of the SNF2 family of helicase/ATPases, is required for chromosome alignment and meiotic spindle organization in metaphase II stage mouse oocytes
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DOI：
10.1016/j.ydbio.2003.12.012
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发表时间：
2004-08-01
影响因子：
2.7
通讯作者：
Eppig, JJ
中科院分区：
文献类型：
--
作者：
De La Fuente, R;Viveiros, MM;Eppig, JJ
ATRX是一种着丝粒异染色质结合蛋白，属于SNF 2解旋酶/ATP酶家族，具有染色质重塑活性。人类ATRX基因突变导致X连锁α-地中海贫血伴智力低下（ATRX）综合征，并与重复DNA序列甲基化的变化相关。我们在这里表明，ATRX也可以调节小鼠卵母细胞减数分裂的关键阶段。在生发泡（GV）阶段，ATRX被发现与转录静止的卵母细胞的核仁周围异染色质边缘。在减数分裂成熟过程中ATRX的磷酸化依赖于钙钙调蛋白激酶（CamKII）的活性。减数分裂恢复也与组蛋白H4在赖氨酸5（H4 K5 Ac）上的脱乙酰化同时发生，而ATRX和在赖氨酸9（H3 K9）上甲基化的组蛋白H3仍然分别结合在浓缩染色体的着丝粒和间质区域。用阿司他丁A（TSA）抑制历史脱乙酰酶（HDAC）会破坏ATRX与超乙酰化染色体着丝粒的结合，导致中期II（MII）染色体排列异常。同样，通过抗体显微注射和RNA干扰（RNAi）选择性消融ATRX对减数分裂的进展没有影响。它对染色体在中期II纺锤体上的排列有严重的后果。这些结果表明，全基因组表观遗传修饰，如全球历史脱乙酰化是必不可少的结合ATRX的着丝粒异染色质。此外，着丝粒ATRX是正确的染色体排列和双极减数分裂中期II纺锤体的组织所必需的。(C)2004年爱思唯尔公司所有权利保留。
ATRX is a centromeric heterochromatin binding protein belonging to the SNF2 family of helicase/ATPases with chromatin remodeling activity. Mutations in the human ATRX gene result in X-linked alpha-thalassaemia with mental retardation (ATRX) syndrome and correlate with changes in methylation of repetitive DNA sequences. We show here that ATRX also functions to regulate key stages of meiosis in mouse oocytes. At the germinal vesicle (GV) stage, ATRX was found associated with the perinucleolar heterochromatin rim in transcriptionally quiescent oocytes. Phosphorylation of ATRX during meiotic maturation is dependent upon calcium calmodulin kinase (CamKII) activity. Meiotic resumption also coincides with deacetylation of histone H4 at lysine 5 (H4K5 Ac) while ATRX and histone H3 methylated on lysine 9 (H3K9) remained bound to the centromeres and interstitial regions of condensing chromosomes, respectively. Inhibition of historic deacetylases (HDACs) with trichostatin A (TSA) disrupted ATRX binding to the centromeres of hyperacetylated chromosomes resulting in abnormal chromosome alignments at metaphase II (MII). Similarly while selective ablation of ATRX by antibody microinjection and RNA interference (RNAi) had no effect on the progression of meiosis. it had severe consequences for the alignment of chromosomes on the metaphase II spindle. These results suggest that genome-wide epigenetic modifications such as global historic deacetylation are essential for the binding of ATRX to centromeric heterochromatin. Moreover, centromeric ATRX is required for correct chromosome alignment and organization of a bipolar meiotic metaphase II spindle. (C) 2004 Elsevier Inc. All rights reseved.