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

被引：225

作者：

Qi, Zhen ^{[1
]}

Li, Yehua ^{[1
]}

Zhao, Bing ^{[1
]}

Xu, Chi ^{[2
,3
]}

Liu, Yuan ^{[1
]}

Li, Haonan ^{[1
]}

Zhang, Bingjie ^{[1
]}

Wang, Xinquan ^{[4
]}

Yang, Xiao ^{[5
]}

Xie, Wei ^{[1
]}

Li, Baojie ^{[6
]}

Han, Jing-Dong Jackie ^{[2
]}

Chen, Ye-Guang ^{[1
]}

机构：

[1] Tsinghua Univ, Sch Life Sci, Tsinghua Peking Ctr Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Biol Sci, Partner Inst Computat Biol, Chinese Acad Sci Max Planck,Key Lab Computat Biol, Shanghai 200031, Peoples R China

[3] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China

[4] Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China

[5] Inst Biotechnol, Genet Lab Dev & Dis, State Key Lab Prote, Beijing 100071, Peoples R China

[6] Shanghai Jiao Tong Univ, Minist Educ, Key Lab Genet Dev & Neuropsychiat Disorders, Bio X Inst, Shanghai 200240, Peoples R China

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

中国国家自然科学基金;

关键词：

SELF-RENEWAL; JUVENILE POLYPOSIS; CRYPT; WNT; EXPRESSION; DIFFERENTIATION; HOMEOSTASIS; PATHWAYS; SIGNALS; CANCER;

D O I：

10.1038/ncomms13824

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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/beta-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.

引用

页数：14

共 68 条

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