The transcription factor NKX2-2 regulates oligodendrocyte differentiation through domain-specific interactions with transcriptional corepressors
The transcription factor NKX2-2 regulates oligodendrocyte differentiation through domain-specific interactions with transcriptional corepressors
复制标题
转录因子 NKX2-2 通过与转录辅阻遏物的域特异性相互作用来调节少突胶质细胞分化
DOI：
10.1074/jbc.ra119.011163
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发表时间：
2020-02-14
影响因子：
4.8
通讯作者：
Qiu, Mengsheng
中科院分区：
文献类型：
--
作者：
Zhang, Chengfu;Huang, Hao;Qiu, Mengsheng
同源结构域蛋白NK2 Homeobox 2(NKX2-2)是一种转录因子，在许多组织中起着控制细胞命运和分化的关键作用。在发育中的中枢神经系统中，这种重要的转录因子发挥转录抑制因子的作用，调控少突胶质细胞(OL)的分化和髓鞘基因的表达，但NKX2-2结构域在这一过程中的作用尚不清楚。在这项研究中，我们利用原位杂交、免疫荧光和免疫共沉淀，确定了介导小鼠NKX2-2抑制功能的结构域，并确定了在OL细胞中与其相互作用的转录辅阻遏子。通过鸡胚胎脊髓的体内电穿孔，我们证明了N-末端Tinman结构域和C-末端结构域通过招募不同的转录抑制因子协同促进OL的分化，包括GRG3增强因子(GRG3)、组蛋白脱乙酰酶1(HDAC1)和DNA甲基转移酶3α(DNMT3A)。我们还观察到NK2特异性结构域抑制C-末端结构域在OL分化中的功能。这些发现描述了不同的NKX2结构域及其在OL分化中的作用，提示NKX2-2通过多个辅助因子和分子机制抑制基因表达来调节分化。
The homeodomain protein NK2 homeobox 2 (NKX2-2) is a transcription factor that plays a critical role in the control of cell fate specification and differentiation in many tissues. In the developing central nervous system, this developmentally important transcription factor functions as a transcriptional repressor that governs oligodendrocyte (OL) differentiation and myelin gene expression, but the roles of various NKX2-2 structural domains in this process are unclear. In this study, using in situ hybridization, immunofluorescence, and coimmunoprecipitation, we determined the structural domains that mediate the repressive functions of murine NKX2-2 and identified the transcriptional corepressors that interact with it in OL cells. Through in ovo electroporation in embryonic chicken spinal cords, we demonstrate that the N-terminal Tinman domain and C-terminal domain synergistically promote OL differentiation by recruiting distinct transcriptional corepressors, including enhancer of split Groucho 3 (GRG3), histone deacetylase 1 (HDAC1), and DNA methyltransferase 3 α (DNMT3A). We also observed that the NK2-specific domain suppresses the function of the C-terminal domain in OL differentiation. These findings delineate the distinct NKX2-2 domains and their roles in OL differentiation and suggest that NKX2-2 regulates differentiation by repressing gene expression via multiple cofactors and molecular mechanisms.