Ray Subir K, Li H Joyce, Metzger Eric, Schüle Roland, Leiter Andrew B
Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Center for Clinical Research, University of Freiburg Medical Center, Freiburg, Germany.
Mol Cell Biol. 2014 Jun;34(12):2308-17. doi: 10.1128/MCB.01600-13. Epub 2014 Apr 14.
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, β-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.
分化所需的基因表达程序取决于DNA结合转录因子和周围的组蛋白修饰。碱性螺旋-环-螺旋（bHLH）蛋白NeuroD1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。RREB1（RAS反应元件结合蛋白1）被鉴定为CtBP共抑制复合物的一个组成部分，它与附近的DNA元件结合，与NeuroD结合并增强NeuroD1靶基因的转录。RREB1的转录激活取决于通过其PXDLS基序募集CtBP及其相关蛋白，包括LSD1。此前尚未对CtBP的转录激活机制进行过表征。在这里，我们发现激活依赖于LSD1的组蛋白H3赖氨酸9（H3K9）去甲基化酶活性，它从二甲基化的H3K9（H3K9Me2）上去除抑制性甲基标记，以促进随后由NeuroD1相关的组蛋白乙酰转移酶P300/CBP相关因子（PCAF）进行的H3K9乙酰化。促胰液素、β-葡萄糖激酶、胰岛素I和胰岛素II基因是NeuroD1在肠道和胰腺内分泌细胞中的四个已知直接靶标，它们都显示出CtBP相关蛋白和PCAF对启动子的类似占据情况，以及H3K9的乙酰化。这项工作可能揭示了一种由CtBP和LSD1选择性调控转录的机制，该机制涉及它们与特定转录因子和辅因子的结合，以驱动组织特异性转录。
