Transcription impairment and cell migration defects in elongator-depleted cells: Implication for familial dysautonomia
Transcription impairment and cell migration defects in elongator-depleted cells: Implication for familial dysautonomia
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DOI：
10.1016/j.molcel.2006.04.017
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发表时间：
2006-05-19
期刊：
影响因子：
16
通讯作者：
Chariot, Alain
中科院分区：
文献类型：
--
作者：
Close, Pierre;Hawkes, Nicola;Chariot, Alain
IKBKAP编码Elongator的一个亚单位，它的突变会导致家族性自主神经障碍(FD)，这是一种具有复杂临床特征的严重神经发育疾病。Elongator以前不仅与转录延长和组蛋白乙酰化有关，还与其他细胞过程有关。在这里，我们使用RNA干扰(RNAi)和来自FD患者的成纤维细胞来识别Elongator靶基因，并研究Elongator在转录中的作用。值得注意的是，虽然Elongator被招募到靶基因和非靶基因中，但在FD细胞中，只有靶基因表现出组蛋白H3的低乙酰化，并通过编码区逐渐降低RNAPII密度。有趣的是，有几个靶基因编码与细胞运动有关的蛋白质。事实上，对IKAP/hELP1 RNAi细胞、FD成纤维细胞和神经细胞衍生细胞的鉴定揭示了Elongator耗竭时这种细胞功能的缺陷。这些结果表明延长器功能缺陷影响了几个基因的转录延长，随之而来的细胞运动性缺陷可能是FD患者神经病理的基础。
Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neuro-developmental disease with complex clinical characteristics. Elongator was previously linked not only with transcriptional elongation and histone acetylation but also with other cellular processes. Here, we used RNA interference (RNAi) and fibroblasts from FD patients to identify Elongator target genes and study the role of Elongator in transcription. Strikingly, whereas Elongator is recruited to both target and nontarget genes, only target genes display histone H3 hypoacetylation and progressively lower RNAPII density through the coding region in FD cells. Interestingly, several target genes encode proteins implicated in cell motility. Indeed, characterization of IKAP/hELP1 RNAi cells, FD fibroblasts, and neuronal cell-derived cells uncovered defects in this cellular function upon Elongator depletion. These results indicate that defects in Elongator function affect transcriptional elongation of several genes and that the ensuing cell motility deficiencies may underlie the neuropathology of FD patients.