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

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

doi:10.1038/s42003-019-0478-3

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

Commun Biol. 2019 Jun 20:2:227. doi: 10.1038/s42003-019-0478-3. eCollection 2019.

Authors

Jane S Weng^{1

2}, Takanori Nakamura¹, Hisashi Moriizumi^{1

2}, Hiroshi Takano³, Ryoji Yao³, Mutsuhiro Takekawa^{1

2}

Affiliations

¹ 1Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639 Japan.
² 2Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8583 Japan.
³ 3Division of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550 Japan.

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.

Keywords: Development; Differentiation; Gene silencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alcohol Oxidoreductases / metabolism*
Animals
Cell Line, Tumor
Co-Repressor Proteins / metabolism*
DNA-Binding Proteins / metabolism*
Epithelium / growth & development
Epithelium / metabolism
Epithelium / pathology
Forkhead Transcription Factors / metabolism
Gene Expression
Gene Silencing
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Lung / growth & development
Lung / metabolism*
Lung / pathology
Mice, Inbred C57BL
Mice, Knockout
Pulmonary Surfactant-Associated Protein B / metabolism*
Pulmonary Surfactant-Associated Protein C / metabolism*
Repressor Proteins / metabolism
Respiratory Insufficiency / metabolism
Respiratory Insufficiency / pathology

Substances

Co-Repressor Proteins
DNA-Binding Proteins
Forkhead Transcription Factors
Foxp1 protein, mouse
Foxp2 protein, mouse
Intracellular Signaling Peptides and Proteins
Mcrip1 protein, mouse
Pulmonary Surfactant-Associated Protein B
Pulmonary Surfactant-Associated Protein C
Repressor Proteins
Alcohol Oxidoreductases
Ctbp2 protein, mouse
C-terminal binding protein