SWI/SNF enzymes promote SOX10- mediated activation of myelin gene expression.
SWI/SNF enzymes promote SOX10- mediated activation of myelin gene expression.
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DOI：
10.1371/journal.pone.0069037
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
de la Serna IL
中科院分区：
文献类型：
--
作者：
Marathe HG;Mehta G;Zhang X;Datar I;Mehrotra A;Yeung KC;de la Serna IL
SOX10是一种与sdn相关的高迁移率（HMG）盒转录调节因子，可促进神经嵴前体分化为雪旺细胞、少突胶质细胞和黑素细胞。髓磷脂是由周围神经系统的雪旺细胞形成的，对神经冲动的传播至关重要。SWI/SNF复合物是ATP依赖性染色质重塑酶，对细胞分化至关重要。最近的研究表明，SWI/SNF复合物的BRG1亚基激活SOX10的表达，并与SOX10相互作用激活OCT6和KROX20的表达，这是雪旺细胞分化的两种转录调节因子。为了确定SWI/SNF酶在编码髓磷脂成分的基因调控中的需求，这是这些转录调节因子的下游，我们将SOX10引入成纤维细胞，诱导表达SWI/SNF atp酶的显性阴性版本，BRM或BRG1。显性阴性BRM和BRG1在ATP结合位点发生突变，抑制需要SWI/SNF功能的基因激活事件。SOX10在NIH 3T3成纤维细胞中异位表达导致内源性雪旺细胞特异性基因髓鞘蛋白零（MPZ）和编码髓鞘碱性蛋白（MBP）的基因被激活。因此，SOX10将这些细胞重新编程为髓磷脂基因表达细胞。KROX20的异位表达不足以激活这些髓磷脂基因。然而，KROX20和SOX10协同激活了MPZ和MBP的表达。显性阴性BRM和BRG1消除了SOX10介导的MPZ和MBP的激活以及SOX10和KROX20对这些基因的协同激活。需要SOX10将BRG1招募到MPZ位点。同样，在永活的雪旺细胞中，BRG1在MPZ位点的SOX10结合位点的募集依赖于SOX10，显性阴性BRG1的表达抑制了这些细胞中MPZ和MBP的表达。因此，SWI/SNF酶与SOX10合作，直接激活编码外周髓磷脂成分的基因。
SOX10 is a Sry-related high mobility (HMG)-box transcriptional regulator that promotes differentiation of neural crest precursors into Schwann cells, oligodendrocytes, and melanocytes. Myelin, formed by Schwann cells in the peripheral nervous system, is essential for propagation of nerve impulses. SWI/SNF complexes are ATP dependent chromatin remodeling enzymes that are critical for cellular differentiation. It was recently demonstrated that the BRG1 subunit of SWI/SNF complexes activates SOX10 expression and also interacts with SOX10 to activate expression of OCT6 and KROX20, two transcriptional regulators of Schwann cell differentiation. To determine the requirement for SWI/SNF enzymes in the regulation of genes that encode components of myelin, which are downstream of these transcriptional regulators, we introduced SOX10 into fibroblasts that inducibly express dominant negative versions of the SWI/SNF ATPases, BRM or BRG1. Dominant negative BRM and BRG1 have mutations in the ATP binding site and inhibit gene activation events that require SWI/SNF function. Ectopic expression of SOX10 in cells derived from NIH 3T3 fibroblasts led to the activation of the endogenous Schwann cell specific gene, myelin protein zero (MPZ) and the gene that encodes myelin basic protein (MBP). Thus, SOX10 reprogrammed these cells into myelin gene expressing cells. Ectopic expression of KROX20 was not sufficient for activation of these myelin genes. However, KROX20 together with SOX10 synergistically activated MPZ and MBP expression. Dominant negative BRM and BRG1 abrogated SOX10 mediated activation of MPZ and MBP and synergistic activation of these genes by SOX10 and KROX20. SOX10 was required to recruit BRG1 to the MPZ locus. Similarly, in immortalized Schwann cells, BRG1 recruitment to SOX10 binding sites at the MPZ locus was dependent on SOX10 and expression of dominant negative BRG1 inhibited expression of MPZ and MBP in these cells. Thus, SWI/SNF enzymes cooperate with SOX10 to directly activate genes that encode components of peripheral myelin.
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影响因子：
5.3
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