The chromatin remodeler SRCAP promotes self-renewal of intestinal stem cells

Buqing Ye; Liuliu Yang; Guomin Qian; Benyu Liu; Xiaoxiao Zhu; Pingping Zhu; Jing Ma; Wei Xie; Huimu Li; Tianku Lu; Yanying Wang; Shuo Wang; Ying Du; Zhimin Wang; Jing Jiang; Jinsong Li; Dongdong Fan; Shu Meng; Jiayi Wu; Yong Tian; Zusen Fan

doi:10.15252/embj.2019103786

The chromatin remodeler SRCAP promotes self-renewal of intestinal stem cells

EMBO J. 2020 Jul 1;39(13):e103786. doi: 10.15252/embj.2019103786. Epub 2020 May 25.

Authors

Buqing Ye^#¹, Liuliu Yang^#^{1

2}, Guomin Qian^#^{1

2}, Benyu Liu^#^{1

2}, Xiaoxiao Zhu^#³, Pingping Zhu¹, Jing Ma⁴, Wei Xie⁴, Huimu Li^{1

2}, Tianku Lu^{1

2}, Yanying Wang¹, Shuo Wang¹, Ying Du¹, Zhimin Wang¹, Jing Jiang⁵, Jinsong Li⁵, Dongdong Fan³, Shu Meng³, Jiayi Wu^{1

2}, Yong Tian^{2

3}, Zusen Fan^{1

2}

Affiliations

¹ Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁴ MOE Key Laboratory of Bioinformatics, Center for Stem Cell Biology and Regenerative Medicine, THU-PKU Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
⁵ State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Genome Tagging Project (GTP) Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

^# Contributed equally.

Abstract

Lgr5⁺ intestinal stem cells (ISCs) exhibit self-renewal and differentiation features under homeostatic conditions, but the mechanisms controlling Lgr5 + ISC self-renewal remain elusive. Here, we show that the chromatin remodeler SRCAP is highly expressed in mouse intestinal epithelium and ISCs. Srcap deletion impairs both self-renewal of ISCs and intestinal epithelial regeneration. Mechanistically, SRCAP recruits the transcriptional regulator REST to the Prdm16 promoter and induces expression of this transcription factor. By activating PPARδ expression, Prdm16 in turn initiates PPARδ signaling, which sustains ISC stemness. Rest or Prdm16 deficiency abrogates the self-renewal capacity of ISCs as well as intestinal epithelial regeneration. Collectively, these data show that the SRCAP-REST-Prdm16-PPARδ axis is required for self-renewal maintenance of Lgr5 + ISCs.

Keywords: REST; SRCAP; PPARδ; intestinal stem cell; self-renewal.

Publication types

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

MeSH terms

Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism*
Animals
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
HEK293 Cells
Humans
Intestinal Mucosa / cytology
Intestinal Mucosa / enzymology*
Mice
Mice, Transgenic
Promoter Regions, Genetic
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Signal Transduction*
Stem Cells / cytology
Stem Cells / enzymology*
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

DNA-Binding Proteins
Lgr5 protein, mouse
Ppard protein, mouse
Prdm16 protein, mouse
RE1-silencing transcription factor
Receptors, Cytoplasmic and Nuclear
Receptors, G-Protein-Coupled
Repressor Proteins
Transcription Factors
Adenosine Triphosphatases

Associated data

GEO/GSE143657
GEO/GSE144267

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding