by Lucas Unger
Yang et al. demonstrate that HHEX is a lineage-restricting transcription factor essential for pancreas specification from foregut progenitors. Through CRISPR-Cas9 loss-of-function screening combined with hiPSC differentiation and single-cell multiomics, the study reveals that deletion of HHEX diverts cells toward liver and duodenal fates. This fate switch is not merely a failure of pancreatic identity but an active reprogramming of lineage potential.
HHEX exerts its function by co-binding with factors FOXA1, FOXA2, and GATA4 to activate pancreatic gene networks and repress hepatic determinants, notably by direct transcriptional inhibition of HNF4A and CDX2. In the absence of HHEX, the FOXA2-HNF4A interaction initiates liver differentiation This work shows how a single gene can act as a developmental switch and guide cell fate.
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Yang D, Cho H, Tayyebi Z, Shukla A, Luo R, Dixon G, Ursu V, Stransky S, Tremmel DM, Sackett SD, Koche R, Kaplan SJ, Li QV, Park J, Zhu Z, Rosen BP, Pulecio J, Shi ZD, Bram Y, Schwartz RE, Odorico JS, Sidoli S, Wright CV, Leslie CS, Huangfu D. CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction
Nat Cell Biol. 2022 Jul;24(7):1064-1076. doi: 10.1038/s41556-022-00946-4.