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A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin

Author

Listed:
  • Wei Gu

    (Weill Cornell Medicine, 1300 York Avenue
    BeiGene (Shanghai) Research & Development Co., Ltd)

  • Xiaofeng Huang

    (Weill Cornell Medicine, 1300 York Avenue)

  • Pratik N. P. Singh

    (Dana-Farber Cancer Institute, 450 Brookline Avenue
    Harvard Medical School, 75 Francis Street)

  • Sanlan Li

    (Weill Cornell Medicine, 1300 York Avenue)

  • Ying Lan

    (Weill Cornell Medicine, 1300 York Avenue)

  • Min Deng

    (Weill Cornell Medicine, 1300 York Avenue)

  • Lauretta A. Lacko

    (Weill Cornell Medicine, 1300 York Avenue
    Weill Cornell Medicine, 1300 York Avenue)

  • Jesus M. Gomez-Salinero

    (Weill Cornell Medicine, 1300 York Avenue)

  • Shahin Rafii

    (Weill Cornell Medicine, 1300 York Avenue)

  • Michael P. Verzi

    (Rutgers University, 145 Bevier Road)

  • Ramesh A. Shivdasani

    (Dana-Farber Cancer Institute, 450 Brookline Avenue
    Harvard Medical School, 75 Francis Street)

  • Qiao Zhou

    (Weill Cornell Medicine, 1300 York Avenue
    Weill Cornell Medicine, 1300 York Avenue)

Abstract

Plasticity among cell lineages is a fundamental, but poorly understood, property of regenerative tissues. In the gut tube, the small intestine absorbs nutrients, whereas the colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screening, we identify MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrains colonic plasticity. MTA2 loss in the adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-occupies DNA with HNF4A, an activating pan-intestinal transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic chromatin, and accumulation on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through an HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages, and their release unleashes plasticity.

Suggested Citation

  • Wei Gu & Xiaofeng Huang & Pratik N. P. Singh & Sanlan Li & Ying Lan & Min Deng & Lauretta A. Lacko & Jesus M. Gomez-Salinero & Shahin Rafii & Michael P. Verzi & Ramesh A. Shivdasani & Qiao Zhou, 2024. "A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47738-y
    DOI: 10.1038/s41467-024-47738-y
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    References listed on IDEAS

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