Sulfotransferase signaling sustains fibroblast identity and antagonizes therapeutic cardiac reprogramming

Abstract

Differentiated cells maintain their identity through active mechanisms that suppress alternative cell fates, but disrupting these barriers can enhance direct reprogramming for organ repair. Among the regulators of cell fate stability, glycosylation-associated genes have emerged as barriers to cardiac reprogramming. Here we show that carbohydrate sulfotransferases are central fate-stabilizing regulators, with CHST7 acting through CD44 to control nuclear JUNB levels, chromatin binding, and downstream transcriptional activity. Integrated RNA-seq and ATAC-seq analyses reveal that CHST7 maintains open chromatin at JUNB- and CTCF-enriched loci while restricting accessibility at MEF2C-enriched regions, collectively reinforcing fibroblast identity and suppressing cardiac fate acquisition. We further identify PIP4K2C as a downstream effector whose inhibition enhances cardiac reprogramming efficiency and improves myocardial repair in vivo. These findings define a sulfotransferase-dependent barrier to cell fate conversion with therapeutic implications for heart regeneration. Cells maintain stable identities that resist conversion into other cell types. Here, the authors show that the sulfotransferase CHST7 stabilizes fibroblast fate via CD44/JUNB signalling, and that its inhibition enhances cardiac reprogramming and improves heart repair.