MCRIP1 promotes the expression of lung-surfactant proteins in mice by disrupting CtBP-mediated epigenetic gene silencing

Jane S Weng,Hiroshi Takano,Takanori Nakamura,Mutsuhiro Takekawa,Ryoji Yao,Hisashi Moriizumi

doi:10.1038/s42003-019-0478-3

Jane S Weng, Hiroshi Takano + Show 4 more

Open Access

https://doi.org/10.1038/s42003-019-0478-3

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Abstract

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 of Mcrip1 in 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.

Highlights

Proper regulation of epigenetic states of chromatin is crucial to achieve tissue-specific gene expression during embryogenesis
In contrast to these in vivo observations, previous studies have shown that Forkhead box P (Foxp)[1] and Foxp[2] proteins interact with transcriptional corepressors including C-terminal-binding protein (CtBP), and synergistically repress, rather than promote, the transcription of genes that are essential for lung development and function[16,20,21,22,23]
We show that MAPK-regulated co-repressor interacting protein 1 (MCRIP1) is highly expressed in lung epithelium during alveolar sac formation, and promotes the expression of the surfactant proteins by preventing Foxp1/2 and CtBP-mediated epigenetic gene silencing

Summary

Introduction

Proper regulation of epigenetic states of chromatin is crucial to achieve tissue-specific gene expression during embryogenesis. 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. Forkhead box P (Foxp) proteins are a family of transcriptional repressors that share a conserved forkhead or winged-helix DNAbinding domain[13] They bind to regulatory elements of a wide range of genes to spatially and temporally control their expression. Foxp1/2 contain the CtBP-binding motif (PxNLV) and have been shown to cooperate with CtBP to downregulate the expression of lung-specific genes such as SP-C, CCSP ( known as CC10), and Nkx2.115,16 These apparently paradoxical findings have, remained unexplained. The role of MCRIP1 in embryonic development is totally unknown

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