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

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 and Qiao Zhou ()
Additional contact information
Wei Gu: Weill Cornell Medicine, 1300 York Avenue
Xiaofeng Huang: Weill Cornell Medicine, 1300 York Avenue
Pratik N. P. Singh: Dana-Farber Cancer Institute, 450 Brookline Avenue
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
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
Qiao Zhou: Weill Cornell Medicine, 1300 York Avenue

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47738-y

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