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

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. Src...

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Bibliographic Details
Published in:	The EMBO journal Vol. 39; no. 13; pp. e103786 - n/a
Main Authors:	Ye, Buqing, Yang, Liuliu, Qian, Guomin, Liu, Benyu, Zhu, Xiaoxiao, Zhu, Pingping, Ma, Jing, Xie, Wei, Li, Huimu, Lu, Tianku, Wang, Yanying, Wang, Shuo, Du, Ying, Wang, Zhimin, Jiang, Jing, Li, Jinsong, Fan, Dongdong, Meng, Shu, Wu, Jiayi, Tian, Yong, Fan, Zusen
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-07-2020 Blackwell Publishing Ltd John Wiley and Sons Inc
Subjects:	Adenosine Triphosphatases - genetics Adenosine Triphosphatases - metabolism Animals Cell differentiation Cell self-renewal Chromatin remodeling DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism EMBO09 EMBO34 Epithelium HEK293 Cells Humans Intestinal Mucosa - cytology Intestinal Mucosa - enzymology intestinal stem cell Intestine Maintenance Mice Mice, Transgenic PPARδ Promoter Regions, Genetic Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - metabolism Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Regeneration Repressor Proteins - genetics Repressor Proteins - metabolism REST self‐renewal Signal Transduction Signaling SRCAP Stem cell transplantation Stem cells Stem Cells - cytology Stem Cells - enzymology Transcription factors Transcription Factors - genetics Transcription Factors - metabolism self‐renewal REST intestinal stem cell SRCAP PPARδ self-renewal
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Summary:	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. Synopsis Chromatin remodeling represents a critical layer of epigenetic regulation in adult stem cells. Here, molecular and in vivo characterization reveals that the chromatin remodeler SRCAP recruits the transcriptional regulator REST to induce Prdm16 transcription, which initiates PPARδ signaling to sustain “stemness” of mouse intestinal stem cells (ISCs). SRCAP is required for self‐renewal maintenance of Lgr5 + ISCs and intestinal epithelial regeneration. SRCAP associates with REST to form a Yeats4‐containing transcriptional activator complex in ISCs, rather than an HCLR repressor complex. SRCAP recruits REST to the Prdm16 promoter to initiate its transcription. Prdm16 transcription factor initiates PPARδ expression to promote self‐renewal of ISCs. Graphical Abstract SRCAP recruitment of transcriptional coregulator REST to the Prdm16 promoter induces its expression, in turn activating PPARδ expression and signaling to sustain ISC self‐renewal.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work
ISSN:	0261-4189 1460-2075
DOI:	10.15252/embj.2019103786