Sirt2 is a novel in vivo downstream target of Nkx2.2 and enhances oligodendroglial cell differentiation
Sirt2 is a novel in vivo downstream target of Nkx2.2 and enhances oligodendroglial cell differentiation
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DOI：
10.1093/jmcb/mjr009
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发表时间：
2011-12-01
影响因子：
5.5
通讯作者：
Nazarali, Adil J.
中科院分区：
文献类型：
--
作者：
Ji, Shaoping;Doucette, J. Ronald;Nazarali, Adil J.
虽然Sirt 2主要在中枢神经系统的少突胶质细胞中表达，但其在少突胶质细胞谱系分化中的作用尚不完全清楚。我们的研究结果表明，转录因子Nkx2.2通过组蛋白去乙酰化酶1（HDAC-1）与Sirt 2启动子结合，Nkx2.2的结合位点靠近Sirt 2基因的起始密码子，Nkx2.2负调控Sirt 2在少突胶质细胞前体细胞系CG 4细胞中的表达。HDAC-1敲除不仅显著减弱Nkx2.2与Sirt 2启动子的结合能力，而且还释放Nkx2.2对Sirt 2表达的抑制。Nkx2.2过表达下调Sirt 2表达并延迟CG 4细胞的分化;相反，Sirt 2的上调不影响Nkx2.2表达水平。通过RNAi敲低Sirt 2或通过Sirt 2活性抑制剂sirtinol抑制Sirt 2可阻断CG 4细胞分化。Sirt 2的过表达在分子和细胞水平上促进CG 4细胞分化，增强髓鞘碱性蛋白的表达并促进细胞突起的生长。我们已经最终证明，Sirt 2增强CG 4少突胶质细胞的分化，并报告了一种新的机制，Nkx2.2通过Sirt 2抑制CG 4少突胶质细胞的分化。
Although Sirt2 is primarily expressed in oligodendrocytes of the central nervous system, its role in oligodendroglial lineage differentiation is not fully understood. Our findings demonstrate that the transcription factor Nkx2.2 binds to the Sirt2 promoter via histone deacetylase 1 (HDAC-1), the binding site for Nkx2.2 maps close to the start codon of the Sirt2 gene, and Nkx2.2 negatively regulates Sirt2 expression in CG4 cells, an oligodendroglial precursor cell line. HDAC-1 knock-down not only significantly attenuates the binding capacity of Nkx2.2 to the Sirt2 promoter but also releases repression of Sirt2 expression by Nkx2.2. Nkx2.2 overexpression down-regulates Sirt2 expression and delays differentiation of CG4 cells; in contrast, up-regulation of Sirt2 does not impact Nkx2.2 expression level. Sirt2 knock-down via RNAi or inhibition of Sirt2 by sirtinol, a Sirt2 activity inhibitor, blocks CG4 cell differentiation. Over-expression of Sirt2 facilitates CG4 cell differentiation at both molecular and cellular levels, enhancing expression of myelin basic protein and facilitating the growth of cell processes. We have conclusively demonstrated that Sirt2 enhances CG4 oligodendroglial differentiation and report a novel mechanism through which Nkx2.2 represses CG4 oligodendroglial differentiation via Sirt2.