CtBP and Associated LSD1 Are Required for Transcriptional Activation by NeuroD1 in Gastrointestinal Endocrine Cells
CtBP and Associated LSD1 Are Required for Transcriptional Activation by NeuroD1 in Gastrointestinal Endocrine Cells
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DOI：
10.1128/mcb.01600-13
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发表时间：
2014-06-01
影响因子：
5.3
通讯作者：
Leiter, Andrew B.
中科院分区：
文献类型：
--
作者：
Ray, Subir K.;Li, H. Joyce;Leiter, Andrew B.
分化所需的基因表达程序取决于DNA结合的转录因子和周围的组蛋白修饰。碱性螺旋-环-螺旋（bHLH）蛋白NeuroD 1的表达仅限于胃肠道（GI）中的内分泌细胞，在那里它对内分泌分化很重要。RREB 1（RAS反应元件结合蛋白1），被鉴定为CtBP辅阻遏物复合物的一个组分，与附近的DNA元件结合，与NeuroD结合，并增强NeuroD 1靶基因的转录。RREB 1的转录激活取决于CtBP及其相关蛋白（包括LSD 1）通过其PXDLS基序的募集。转录激活CtBP的机制还没有以前的特点。在这里，我们发现激活依赖于LSD 1的组蛋白H3赖氨酸9（H3 K9）去甲基化酶活性，其从二甲基化的H3 K9（H3 K9 Me 2）中去除抑制性甲基标记，以促进随后的H3 K9通过NeuroD 1相关的组蛋白乙酰转移酶，P300/CBP相关因子（PCAF）进行乙酰化。肠和胰腺内分泌细胞中NeuroD 1的四个已知直接靶点--促胰液素、β-葡萄糖激酶、胰岛素I和胰岛素II基因均显示出类似的CtBP相关蛋白和PCAF启动子占用率，以及H3 K9的乙酰化。这项工作可能表明CtBP和LSD 1选择性调节转录的机制，涉及它们与特定转录因子和辅因子的关联，以驱动组织特异性转录。
Gene expression programs required for differentiation depend on both DNA-bound transcription factors and surrounding histone modifications. Expression of the basic helix-loop-helix (bHLH) protein NeuroD1 is restricted to endocrine cells in the gastrointestinal (GI) tract, where it is important for endocrine differentiation. RREB1 (RAS-responsive element binding protein 1), identified as a component of the CtBP corepressor complex, binds to nearby DNA elements to associate with NeuroD and potentiate transcription of a NeuroD1 target gene. Transcriptional activation by RREB1 depends on recruitment of CtBP with its associated proteins, including LSD1, through its PXDLS motifs. The mechanism of transcriptional activation by CtBP has not been previously characterized. Here we found that activation was dependent on the histone H3 lysine 9 (H3K9) demethylase activity of LSD1, which removes repressive methyl marks from dimethylated H3K9 (H3K9Me2), to facilitate subsequent H3K9 acetylation by the NeuroD1-associated histone acetyltransferase, P300/CBP-associated factor (PCAF). The secretin, beta-glucokinase, insulin I, and insulin II genes, four known direct targets of NeuroD1 in intestinal and pancreatic endocrine cells, all show similar promoter occupancy by CtBP-associated proteins and PCAF, with acetylation of H3K9. This work may indicate a mechanism for selective regulation of transcription by CtBP and LSD1 involving their association with specific transcription factors and cofactors to drive tissue-specific transcription.