Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors
Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors
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DOI：
10.1016/j.cell.2006.12.038
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发表时间：
2007-02-09
期刊：
影响因子：
64.5
通讯作者：
Rosenfeld, Michael G.
中科院分区：
文献类型：
--
作者：
Garcia-Bassets, Ivan;Kwon, Young-Soo;Rosenfeld, Michael G.
核受体经历辅阻遏物-辅激活物交换所需的配体依赖性构象变化，但是否实际需要特定的表观遗传标志来施加基因激活的配体依赖性仍然未知。在这里，我们报告了一个意想不到的和一般性的策略，这是基于对特定的抑制性组蛋白甲基转移酶（HMT）的要求，以施加基因特异性的看门人功能，防止配体的核受体和其他类别的调节转录因子结合到它们的靶基因启动子，并在没有刺激信号的情况下引起组成型基因激活。这种策略至少部分基于HMT依赖性抑制性组蛋白密码，要求特定的组蛋白去甲基化酶，包括LSD 1，以允许受调节的基因表达的配体和信号依赖性激活。这些事件将组蛋白编码的抑制性甲基化组分与广泛使用的策略联系起来，该策略通过生理调节的转录因子来规避病理性组成型基因诱导。
Nuclear receptors undergo ligand-dependent conformational changes that are required for corepressor-coactivator exchange, but whether there is an actual requirement for specific epigenetic landmarks to impose ligand dependency for gene activation remains unknown. Here we report an unexpected and general strategy that is based on the requirement for specific cohorts of inhibitory histone methyltransferases (HMTs) to impose gene-specific gatekeeper functions that prevent unliganded nuclear receptors and other classes of regulated transcription factors from binding to their target gene promoters and causing constitutive gene activation in the absence of stimulating signals. This strategy, based at least in part on an HMT-dependent inhibitory histone code, imposes a requirement for specific histone demethylases, including LSD1, to permit ligand- and signal-dependent activation of regulated gene expression. These events link an inhibitory methylation component of the histone code to a broadly used strategy that circumvents pathological constitutive gene induction by physiologically regulated transcription factors.