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 Collections 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 Pet accessories broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages, and their release unleashes plasticity.