Tcf21 functions as a rate-limiting factor during visceral adipose tissue development [single-cell RNA-seq]

The location of visceral adipose tissue (VAT) suggests specific developmental regulation. Our lineage-tracing study identified the specific expression of Tcf21 in VAT progenitor cells (PCs). Tcf21 lineage PCs (LPs) actively differentiate into adipocytes during development but not in adulthood. Bulk RNAseq identified dynamic gene expression of Tcf21 LPs, including enrichment of pro-mitotic and pro-adipogenic genes during development and increased expression of a set of fibrotic genes in obese mice. ATACseq revealed chromatin remodeling that was highly correlated with gene expression dynamics. Using a novel computational approach via integrative analysis of gene expression and chromatin accessibility profiles, an underlying gene regulatory network was reconstructed. Single-cell RNAseq identified subpopulations of Tcf21 LPs including mesothelial and interstitial subpopulations. Using an inducible Tcf21 knockout line, we identified that loss of Tcf21 promoted the adipogenesis and developmental progress of Tcf21 LPs, leading to improved metabolic health of mice after HFD challenge. Mechanistic studies showed that Tcf21 mainly targets enhancers, and the inhibitory effect of Tcf21 on adipogenesis is at least partially through the increasing Dlk1 expression. Single-cell RNA-seq