MCRIP1 promotes the expression of lung-surfactant proteins in mice by disrupting CtBP-mediated epigenetic gene silencing
MCRIP1 promotes the expression of lung-surfactant proteins in mice by disrupting CtBP-mediated epigenetic gene silencing
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MCRIP1 通过破坏 CtBP 介导的表观遗传基因沉默来促进小鼠肺表面活性蛋白的表达
DOI：
10.1038/s42003-019-0478-3
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发表时间：
2019
影响因子：
5.9
通讯作者：
Takekawa Mutsuhiro
中科院分区：
文献类型：
--
作者：
Weng Jane S.;Nakamura Takanori;Moriizumi Hisashi;Takano Hiroshi;Yao Ryoji;Takekawa Mutsuhiro
正确调控染色质的表观遗传状态是胚胎发生过程中实现组织特异性基因表达的关键。肺特异性基因产物，表面活性蛋白B（SP-B B）和C（SP-C），在肺泡上皮细胞中合成并防止肺泡塌陷。然而，这些表面活性蛋白的表观遗传调控仍然未知。在这里，我们报告说，MCRIP 1，调节CtBP转录辅阻遏物，促进SP-B和SP-C的表达，防止CtBP介导的表观遗传基因沉默。纯合子缺陷的Mcrip 1在小鼠中引起致命的呼吸窘迫，由于这些表面活性蛋白的异常转录抑制。我们发现MCRIP 1干扰CtBP与肺富集转录抑制因子Foxp 1和Foxp 2的相互作用，从而阻止CtBP辅抑制因子复合物募集到SP-B和SP-C启动子，并使它们保持在活性染色质状态。我们的研究结果揭示了一种分子机制，通过这种机制，细胞可以防止无意中的基因沉默，以确保器官发生过程中组织特异性的基因表达。
Proper regulation of epigenetic states of chromatin is crucial to achieve tissue-specific gene expression during embryogenesis. The lung-specific gene products, surfactant proteins B (SP-B) and C (SP-C), are synthesized in alveolar epithelial cells and prevent alveolar collapse. Epigenetic regulation of these surfactant proteins, however, remains unknown. Here we report that MCRIP1, a regulator of the CtBP transcriptional co-repressor, promotes the expression of SP-B and SP-C by preventing CtBP-mediated epigenetic gene silencing. Homozygous deficiency ofMcrip1in mice causes fatal respiratory distress due to abnormal transcriptional repression of these surfactant proteins. We found that MCRIP1 interferes with interactions of CtBP with the lung-enriched transcriptional repressors, Foxp1 and Foxp2, thereby preventing the recruitment of the CtBP co-repressor complex to the SP-B and SP-C promoters and maintaining them in an active chromatin state. Our findings reveal a molecular mechanism by which cells prevent inadvertent gene silencing to ensure tissue-specific gene expression during organogenesis.