Identification of CHD7S as a novel splicing variant of CHD7 with functions similar and antagonistic to those of the full-length CHD7L
Identification of CHD7S as a novel splicing variant of CHD7 with functions similar and antagonistic to those of the full-length CHD7L
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DOI：
10.1111/j.1365-2443.2012.01606.x
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发表时间：
2012-07-01
期刊：
影响因子：
2.1
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
--
作者：
Kita, Yasuyuki;Nishiyama, Masaaki;Nakayama, Keiichi I.
CHD7 是 ATP 依赖性染色质重塑酶染色质结构域解旋酶 DNA 结合家族的九个成员之一。 CHD7 突变会导致 CHARGE 综合征，这是一种以多种器官畸形为特征的人类疾病。我们现在已经鉴定了一种新的 CHD7 转录本，它是通过外显子 6 的选择性剪接生成的。这种变异转录本（称为 CHD7S）编码的蛋白质缺乏两个染色质结构域之一以及全长蛋白质 (CHD7L) 的解旋酶/ATP 酶结构域、DNA 结合结构域和 BRK 结构域。发现 CHD7S 以依赖于核仁定位信号的方式特异性定位于核仁。 CHD7S 以及 CHD7L 的过度表达导致 45S 前体 rRNA 产量增加。相反，通过RNA干扰去除CHD7S和CHD7L，比单独去除CHD7L更能抑制45S前体rRNA的产生和细胞增殖。此外，我们发现，与 CHD7L 一样，CHD7S 与核质中的 Sox2 结合。然而，出乎意料的是，CHD7L 的过度表达促进了 Sox2 介导的转录调节，而 CHD7S 的过度表达却抑制了它。这些结果表明CHD7S分别在核仁和核质中与CHD7L协同或拮抗地发挥功能。
CHD7 is one of the nine members of the chromodomain helicase DNA-binding family of ATP-dependent chromatin remodeling enzymes. Mutations in CHD7 give rise to CHARGE syndrome, a human condition characterized by malformation of various organs. We have now identified a novel transcript of CHD7 that is generated by alternative splicing of exon 6. The protein encoded by this variant transcript (termed CHD7S) lacks one of the two chromodomains as well as the helicase/ATPase domain, DNA-binding domain and BRK domains of the full-length protein (CHD7L). CHD7S was found to localize specifically to the nucleolus in a manner dependent on a nucleolar localization signal. Over-expression of CHD7S, as well as that of CHD7L, resulted in an increase in 45S precursor rRNA production. Conversely, depletion of both CHD7S and CHD7L by RNA interference inhibited both 45S precursor rRNA production and cell proliferation to a greater extent than did depletion of CHD7L alone. Furthermore, we found that, like CHD7L, CHD7S binds to Sox2 in the nucleoplasm. Unexpectedly, however, whereas over-expression of CHD7L promoted Sox2-mediated transcriptional regulation, over-expression of CHD7S suppressed it. These results indicate that CHD7S functions cooperatively or antagonistically with CHD7L in the nucleolus and nucleoplasm, respectively.