Opposing LSD1 complexes function in developmental gene activation and repression programmes
Opposing LSD1 complexes function in developmental gene activation and repression programmes
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DOI：
10.1038/nature05671
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发表时间：
2007-04-19
期刊：
影响因子：
64.8
通讯作者：
Rosenfeld, Michael G.
中科院分区：
文献类型：
--
作者：
Wang, Jianxun;Scully, Kathleen;Rosenfeld, Michael G.
精确控制转录程序的后生动物的发展是由酶活性的共调节复合物，加上表观遗传策略调制。有一件事仍然不清楚的是，组蛋白修饰酶家族的特定成员，如组蛋白甲基转移酶和脱甲基酶，如何在体内同时协调不同的发育基因激活和抑制程序。在这里，我们报告了组蛋白赖氨酸脱甲基酶，LSD 1-一个组成部分的CoREST-CtBP共阻遏复合物-是需要在垂体器官形成后期细胞谱系的确定和分化。LSD 1似乎主要作用于靶基因激活程序，以及基因阻遏程序，基于募集不同的含LSD 1的共激活物或共阻遏物复合物。LSD 1依赖性基因阻遏程序可以在发育后期通过诱导ZEB 1表达而扩展，ZEB 1是一种Kruppel样阻遏物，可以充当招募含LSD 1的CoREST-CtBP共阻遏物复合物的分子信标，导致抑制额外的基因组，如Gh，其先前需要LSD 1进行激活。这些研究结果表明，时间模式的LSD 1复合物的特定组件的表达调节基因调控程序在许多哺乳动物器官。
Precise control of transcriptional programmes underlying metazoan development is modulated by enzymatically active co-regulatory complexes, coupled with epigenetic strategies. One thing that remains unclear is how specific members of histone modification enzyme families, such as histone methyltransferases and demethylases, are used in vivo to simultaneously orchestrate distinct developmental gene activation and repression programmes. Here, we report that the histone lysine demethylase, LSD1 - a component of the CoREST-CtBP co- repressor complex - is required for late cell-lineage determination and differentiation during pituitary organogenesis. LSD1 seems to act primarily on target gene activation programmes, as well as in gene repression programmes, on the basis of recruitment of distinct LSD1-containing co- activator or co- repressor complexes. LSD1-dependent gene repression programmes can be extended late in development with the induced expression of ZEB1, a Kruppel-like repressor that can act as a molecular beacon for recruitment of the LSD1-containing CoREST-CtBP co- repressor complex, causing repression of an additional cohort of genes, such as Gh, which previously required LSD1 for activation. These findings suggest that temporal patterns of expression of specific components of LSD1 complexes modulate gene regulatory programmes in many mammalian organs.