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

Wei Gu1, Hua Wang2, Xiaofeng Huang1, Judith Kraiczy3, Pratik N P Singh3, Charles Ng4, Sezin Dagdeviren5, Sean Houghton1, Oscar Pellon-Cardenas6, Ying Lan1, Yaohui Nie1, Jiaoyue Zhang1, Kushal K Banerjee3, Emily J Onufer7, Brad W Warner7, Jason Spence8, Ellen Scherl4, Shahin Rafii1, Richard T Lee5, Michael P Verzi6, David Redmond1, Randy Longman4, Kristian Helin9, Ramesh A Shivdasani3, Qiao Zhou10

  1. Division of Regenerative Medicine & Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
  2. Cell Biology Program and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, 430 E 67th Street, New York, NY 10065, USA.
  3. Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
  4. Jill Roberts Center for Inflammatory Bowel Disease, Weill Cornell Medicine, 1283 York Avenue, New York, NY 10065, USA.
  5. Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
  6. Department of Genetics, Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA.
  7. Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
  8. Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
  9. Cell Biology Program and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, 430 E 67th Street, New York, NY 10065, USA; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N 2200, Denmark; The Novo Nordisk Foundation for Stem Cell Biology (Danstem), University of Copenhagen, Copenhagen N 2200, Denmark.
  10. Division of Regenerative Medicine & Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA. Electronic address: jqz4001@med.cornell.edu.

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.

Presented By Wei Gu | ORCID iD

Cell & Developmental Bio, Genetics & Genome BiologyNicholas Liao2022-01 (Jan)