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BMP restricts stemness of intestinal Lgr5+ stem cells by directly suppressing their signature genes

Author

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  • Zhen Qi

    (The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Yehua Li

    (The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Bing Zhao

    (The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Chi Xu

    (Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Graduate University of Chinese Academy of Sciences)

  • Yuan Liu

    (The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Haonan Li

    (The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Bingjie Zhang

    (The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Xinquan Wang

    (Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Tsinghua University)

  • Xiao Yang

    (State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology)

  • Wei Xie

    (The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Baojie Li

    (Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)

  • Jing-Dong Jackie Han

    (Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Ye-Guang Chen

    (The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

Abstract

The intestinal epithelium possesses a remarkable self-renewal ability, which is mediated by actively proliferating Lgr5+ stem cells. Bone morphogenetic protein (BMP) signalling represents one major counterforce that limits the hyperproliferation of intestinal epithelium, but the exact mechanism remains elusive. Here we demonstrate that epithelial BMP signalling plays an indispensable role in restricting Lgr5+ stem cell expansion to maintain intestinal homeostasis and prevent premalignant hyperproliferation on damage. Mechanistically, BMP inhibits stemness of Lgr5+ stem cells through Smad-mediated transcriptional repression of a large number of stem cell signature genes, including Lgr5, and this effect is independent of Wnt/β-catenin signalling. Smad1/Smad4 recruits histone deacetylase HDAC1 to the promoters to repress transcription, and knockout of Smad4 abolishes the negative effects of BMP on stem cells. Our findings therefore demonstrate that epithelial BMP constrains the Lgr5+ stem cell self-renewal via Smad-mediated repression of stem cell signature genes to ensure proper homeostatic renewal of intestinal epithelium.

Suggested Citation

  • Zhen Qi & Yehua Li & Bing Zhao & Chi Xu & Yuan Liu & Haonan Li & Bingjie Zhang & Xinquan Wang & Xiao Yang & Wei Xie & Baojie Li & Jing-Dong Jackie Han & Ye-Guang Chen, 2017. "BMP restricts stemness of intestinal Lgr5+ stem cells by directly suppressing their signature genes," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms13824
    DOI: 10.1038/ncomms13824
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    Cited by:

    1. Jong Hoon Won & Jacob S. Choi & Joon-Il Jun, 2022. "CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Marta Kapalczynska & Manqiang Lin & Jeroen Maertzdorf & Julian Heuberger & Stefanie Muellerke & Xiangsheng Zuo & Ramon Vidal & Imad Shureiqi & Anne-Sophie Fischer & Sascha Sauer & Hilmar Berger & Evel, 2022. "BMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Mara Martín-Alonso & Sharif Iqbal & Pia M. Vornewald & Håvard T. Lindholm & Mirjam J. Damen & Fernando Martínez & Sigrid Hoel & Alberto Díez-Sánchez & Maarten Altelaar & Pekka Katajisto & Alicia G. Ar, 2021. "Smooth muscle-specific MMP17 (MT4-MMP) regulates the intestinal stem cell niche and regeneration after damage," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Simone Isling Pærregaard & Line Wulff & Sophie Schussek & Kristoffer Niss & Urs Mörbe & Johan Jendholm & Kerstin Wendland & Anna T. Andrusaite & Kevin F. Brulois & Robert J. B. Nibbs & Katarzyna Sitni, 2023. "The small and large intestine contain related mesenchymal subsets that derive from embryonic Gli1+ precursors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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