XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks
XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks
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DOI：
10.1016/j.molcel.2007.06.011
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发表时间：
2007-07-06
期刊：
影响因子：
16
通讯作者：
Dynlacht, Brian David
中科院分区：
文献类型：
--
作者：
Acosta-Alvear, Diego;Zhou, Yiming;Dynlacht, Brian David
利用全基因组的方法，我们已经阐明了XBP1转录因子在骨骼肌和分泌细胞中的调控电路，XBP1转录因子是哺乳动物未折叠蛋白反应(UPR)的关键效应因子。我们确定了一组核心基因，这些基因涉及所有细胞类型以及组织和条件特定靶点的内质网功能的结构性维持。此外，我们确定了一组意想不到的靶点，将XBP1与神经退行性疾病和肌肉退行性疾病以及DNA损伤和修复途径联系起来。值得注意的是，我们发现XBP1通过不同的序列基序调节不同的功能靶点。此外，我们发现分化的关键调控因子Mist1是XBP1的一个重要靶点，为XBP1功能丧失相关的发育缺陷提供了解释。我们的结果提供了XBP1在不同细胞类型中调控路线图的详细图，以及对XBP1未知功能的洞察。
Using genome-wide approaches, we have elucidated the regulatory circuitry governed by the XBP1 transcription factor, a key effector of the mammalian unfolded protein response (UPR), in skeletal muscle and secretory cells. We identified a core group of genes involved in constitutive maintenance of ER function in all cell types and tissue- and condition-specific targets. In addition, we identified a cadre of unexpected targets that link XBP1 to neuro-degenerative and myodegenerative diseases, as well as to DNA damage and repair pathways. Remarkably, we found that XBP1 regulates functionally distinct targets through different sequence motifs. Further, we identified Mist1, a critical regulator of differentiation, as an important target of XBP1, providing an explanation for developmental defects associated with XBP1 loss of function. Our results provide a detailed picture of the regulatory roadmap governed by XBP1 in distinct cell types as well as insight into unexplored functions of XBP1.