title: BMP restricts stemness of intestinal Lgr5+stem cells by directly suppressing their signature genes.
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.
authors.affiliation: The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qi
authors.affiliation: The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yehua
authors.initials: Y
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhao
authors.affiliation: 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, Shanghai 200031, China.|Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Haonan
authors.initials: H
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Bingjie
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xinquan
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
authors.affiliation: 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, Shanghai 200031, China.
authors.forename: Jing-Dong Jackie
authors.initials: JJ
authors.lastname: Han
authors.affiliation: The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D049109:Cell Proliferation / Q000235:genetics / Q000528:radiation effects; D000066673:Cell Self Renewal / Q000528:radiation effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000528:radiation effects; D006655:Histone Deacetylases / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D007422:Intestines / Q000166:cytology*; D008297:Male; D008810:Mice, Inbred C57BL; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000528:radiation effects; D011839:Radiation, Ionizing; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012038:Regeneration / Q000528:radiation effects; D051785:Smad Proteins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051785:Smad Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D006655:Histone Deacetylases