SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling

Wei Gu; Hua Wang; Xiaofeng Huang; Judith Kraiczy; Pratik N.P. Singh; Charles Ng; Sezin Dagdeviren; Sean Houghton; Oscar Pellon-Cardenas; Ying Lan; Yaohui Nie; Jiaoyue Zhang; Kushal K. Banerjee; Emily J. Onufer; Brad W. Warner; Jason Spence; Ellen Scherl; Shahin Rafii; Richard T. Lee; Michael P. Verzi; David Redmond; Randy Longman; Kristian Helin; Ramesh A. Shivdasani; Qiao Zhou

doi:10.1016/j.stem.2021.09.004

SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling

Wei Gu
, Hua Wang
, Xiaofeng Huang
, Judith Kraiczy
, Pratik N.P. Singh
, Charles Ng
, Sezin Dagdeviren
, Sean Houghton
, Oscar Pellon-Cardenas
, Ying Lan
, Yaohui Nie
, Jiaoyue Zhang
, Kushal K. Banerjee
, Emily J. Onufer
, Brad W. Warner
, Jason Spence
, Ellen Scherl
, Shahin Rafii
, Richard T. Lee
, Michael P. Verzi

David Redmond, Randy Longman, Kristian Helin, Ramesh A. Shivdasani, Qiao Zhou^*

^*Corresponding author for this work

Helin Group

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not well understood. The small and large intestines differ markedly in cell composition and function, reflecting their distinct stem cell populations. Here we show that SATB2, a colon-restricted chromatin factor, singularly preserves LGR5⁺ adult colonic stem cell and epithelial identity in mice and humans. Satb2 loss in adult mice leads to stable conversion of colonic stem cells into small intestine ileal-like stem cells and replacement of the colonic mucosa with one that resembles the ileum. Conversely, SATB2 confers colonic properties on the mouse ileum. Human colonic organoids also adopt ileal characteristics upon SATB2 loss. SATB2 regulates colonic identity in part by modulating enhancer binding of the intestinal transcription factors CDX2 and HNF4A. Our study uncovers a conserved core regulator of colonic stem cells able to mediate cross-tissue plasticity in mature intestines.

Original language	English
Journal	Cell Stem Cell
Volume	29
Issue number	1
Pages (from-to)	101-115.e10
Number of pages	26
ISSN	1934-5909
DOIs	https://doi.org/10.1016/j.stem.2021.09.004
Publication status	Published - 2022

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Funding

We thank the WCM Epigenetics Core (Jenny Xiang), WCM Flow Cytometry Core (Jason McCormick and Tomas Baumgartner), Tri-Institutional Stem cell Derivation Core (Raphael Lis and Tyler Lu), MSKCC Center for Epigenetics Research (Ruifang Li), and Harvard Genome Modification Facility (Lin Wu) for excellent technical assistance. We are grateful to Shariq Madha for assistance with computational analyses, Dr. Frederick J. de Sauvage for providing Lgr5 DTRGFP mice, Drs. James Wells and Todd Evans for discussions, and Jonathan Colarusso for editing the manuscript. This work was supported by Weill Cornell Medicine funds (to Q.Z.), a Tri-Institutional Stem Cell grant (to Q.Z. and K.H.), NIH/NIDDK grants (1R01DK125817 to Q.Z. 1R01DK082889 to R.A.S., 1R01DK107396 to R.T.L., and R01DK121915 to M.P.V.), a NNF Center grant for stem cell biology ( NNF17CC0027852 to K.H.), and an MSKCC support grant ( NIH P30 CA008748 ). J.K. is grateful for support from the Deutsche Forschungsgemeinschaft (DFG) ( KR 5451/1-1 ). We thank the WCM Epigenetics Core (Jenny Xiang), WCM Flow Cytometry Core (Jason McCormick and Tomas Baumgartner), Tri-Institutional Stem cell Derivation Core (Raphael Lis and Tyler Lu), MSKCC Center for Epigenetics Research (Ruifang Li), and Harvard Genome Modification Facility (Lin Wu) for excellent technical assistance. We are grateful to Shariq Madha for assistance with computational analyses, Dr. Frederick J. de Sauvage for providing Lgr5DTRGFP mice, Drs. James Wells and Todd Evans for discussions, and Jonathan Colarusso for editing the manuscript. This work was supported by Weill Cornell Medicine funds (to Q.Z.), a Tri-Institutional Stem Cell grant (to Q.Z. and K.H.), NIH/NIDDK grants (1R01DK125817 to Q.Z. 1R01DK082889 to R.A.S. 1R01DK107396 to R.T.L. and R01DK121915 to M.P.V.), a NNF Center grant for stem cell biology (NNF17CC0027852 to K.H.), and an MSKCC support grant (NIH P30 CA008748). J.K. is grateful for support from the Deutsche Forschungsgemeinschaft (DFG) (KR 5451/1-1). W.G. and Q.Z. designed all experiments, interpreted data, and wrote the manuscript. W.G. performed all experiments. H.W. performed ChIP and enhancer analyses with help from P.N.P.S. and S.H. X.H. and D.R. performed scRNA-seq analysis. X.H. and W.G. performed bulk RNA-seq analysis. J.K. and R.A.S. provided bulk RNA-seq raw data of Eed deletion and early time course experiments. S.D. participated in the functional nutrient absorption studies with contributions from E.J.O. B.W.W. O.P.-C. and M.P.V. C.N. E.S. and R.T.L. provided human samples and advice regarding data interpretation. Y.L. Y.N. and J.Z. contributed to independent validation of data. R.A.S. K.H. and S.R. contributed to experimental design, discussed experiments, and edited the manuscript. A patent application related to this work is pending at Weill Cornell Medicine.

Keywords

SATB2, intestine regeneration, colonic mucosa, stem cell conversion, enhancer remodelingintestine

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10.1016/j.stem.2021.09.004

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741647/pdf/nihms-1739927.pdfLicence: Other

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Cite this

Gu, W., Wang, H., Huang, X., Kraiczy, J., Singh, P. N. P., Ng, C., Dagdeviren, S., Houghton, S., Pellon-Cardenas, O., Lan, Y., Nie, Y., Zhang, J., Banerjee, K. K., Onufer, E. J., Warner, B. W., Spence, J., Scherl, E., Rafii, S., Lee, R. T., ... Zhou, Q. (2022). SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling. Cell Stem Cell, 29(1), 101-115.e10. https://doi.org/10.1016/j.stem.2021.09.004

Gu, W, Wang, H, Huang, X, Kraiczy, J, Singh, PNP, Ng, C, Dagdeviren, S, Houghton, S, Pellon-Cardenas, O, Lan, Y, Nie, Y, Zhang, J, Banerjee, KK, Onufer, EJ, Warner, BW, Spence, J, Scherl, E, Rafii, S, Lee, RT, Verzi, MP, Redmond, D, Longman, R, Helin, K, Shivdasani, RA & Zhou, Q 2022, 'SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling', Cell Stem Cell, vol. 29, no. 1, pp. 101-115.e10. https://doi.org/10.1016/j.stem.2021.09.004

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abstract = "Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not well understood. The small and large intestines differ markedly in cell composition and function, reflecting their distinct stem cell populations. Here we show that SATB2, a colon-restricted chromatin factor, singularly preserves LGR5+ adult colonic stem cell and epithelial identity in mice and humans. Satb2 loss in adult mice leads to stable conversion of colonic stem cells into small intestine ileal-like stem cells and replacement of the colonic mucosa with one that resembles the ileum. Conversely, SATB2 confers colonic properties on the mouse ileum. Human colonic organoids also adopt ileal characteristics upon SATB2 loss. SATB2 regulates colonic identity in part by modulating enhancer binding of the intestinal transcription factors CDX2 and HNF4A. Our study uncovers a conserved core regulator of colonic stem cells able to mediate cross-tissue plasticity in mature intestines.",

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author = "Wei Gu and Hua Wang and Xiaofeng Huang and Judith Kraiczy and Singh, \{Pratik N.P.\} and Charles Ng and Sezin Dagdeviren and Sean Houghton and Oscar Pellon-Cardenas and Ying Lan and Yaohui Nie and Jiaoyue Zhang and Banerjee, \{Kushal K.\} and Onufer, \{Emily J.\} and Warner, \{Brad W.\} and Jason Spence and Ellen Scherl and Shahin Rafii and Lee, \{Richard T.\} and Verzi, \{Michael P.\} and David Redmond and Randy Longman and Kristian Helin and Shivdasani, \{Ramesh A.\} and Qiao Zhou",

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AU - Singh, Pratik N.P.

AU - Ng, Charles

AU - Dagdeviren, Sezin

AU - Houghton, Sean

AU - Pellon-Cardenas, Oscar

AU - Lan, Ying

AU - Nie, Yaohui

AU - Zhang, Jiaoyue

AU - Banerjee, Kushal K.

AU - Onufer, Emily J.

AU - Warner, Brad W.

AU - Spence, Jason

AU - Scherl, Ellen

AU - Rafii, Shahin

AU - Lee, Richard T.

AU - Verzi, Michael P.

AU - Redmond, David

AU - Longman, Randy

AU - Helin, Kristian

AU - Shivdasani, Ramesh A.

AU - Zhou, Qiao

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N2 - Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not well understood. The small and large intestines differ markedly in cell composition and function, reflecting their distinct stem cell populations. Here we show that SATB2, a colon-restricted chromatin factor, singularly preserves LGR5+ adult colonic stem cell and epithelial identity in mice and humans. Satb2 loss in adult mice leads to stable conversion of colonic stem cells into small intestine ileal-like stem cells and replacement of the colonic mucosa with one that resembles the ileum. Conversely, SATB2 confers colonic properties on the mouse ileum. Human colonic organoids also adopt ileal characteristics upon SATB2 loss. SATB2 regulates colonic identity in part by modulating enhancer binding of the intestinal transcription factors CDX2 and HNF4A. Our study uncovers a conserved core regulator of colonic stem cells able to mediate cross-tissue plasticity in mature intestines.

AB - Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not well understood. The small and large intestines differ markedly in cell composition and function, reflecting their distinct stem cell populations. Here we show that SATB2, a colon-restricted chromatin factor, singularly preserves LGR5+ adult colonic stem cell and epithelial identity in mice and humans. Satb2 loss in adult mice leads to stable conversion of colonic stem cells into small intestine ileal-like stem cells and replacement of the colonic mucosa with one that resembles the ileum. Conversely, SATB2 confers colonic properties on the mouse ileum. Human colonic organoids also adopt ileal characteristics upon SATB2 loss. SATB2 regulates colonic identity in part by modulating enhancer binding of the intestinal transcription factors CDX2 and HNF4A. Our study uncovers a conserved core regulator of colonic stem cells able to mediate cross-tissue plasticity in mature intestines.

KW - SATB2, intestine regeneration, colonic mucosa, stem cell conversion, enhancer remodelingintestine

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