Biology subjects

Yang, Z. F.

Publications and source records attributed to Yang, Z. F..

3 recordsLinked to original sources

bioRxiv2025

Gene regulatory network determinants of rapid recall in human memory CD4+ T cells

Rapid recall is the hallmark of memory T cells. While naive cells require days to mount effector responses to new threats, antigen-experienced memory cells produce cytokines within hours of repeat encounter. Memory establishment and the control of rapid recall across lifespan is poorly understood. Epigenetic poising is a likely mechanism. Compared to naive, memory cells exhibit enhanced chromatin accessibility proximal to rapid recall genes, but the transcription factors (TFs) that establish, maintain and utilize these putative regulatory elements are unknown. We leverage single-nuclei (sn)multiome-seq (snRNA-seq and snATAC-seq) to characterize the dynamic activation responses of CD4+ T cell subsets and (2) reconstruct the underlying gene regulatory networks. Memory-associated TFs (MAF, PRDM1, RUNX2, SMAD3, KLF6) were predicted to orchestrate rapid recall. KLF6 binding to its predicted target genes was confirmed by ChIP-seq, while the memory-associated activities of all five factors replicated in independent scRNA-seq studies. Integrating GWAS data, we nominate CD4+ T cell populations and gene regulatory mechanisms that might underly genetic risk to immune-mediated diseases.

systems biology↗

bioRxiv2024

Nutrient starvation activates ECM remodeling gene enhancers associated with inflammatory bowel disease risk in fibroblasts

Nutrient deprivation induces a reversible cell cycle arrest state termed quiescence, which often accompanies transcriptional silencing and chromatin compaction. Paradoxically, nutrient deprivation is associated with activated fibroblast states in pathological microenvironments in which fibroblasts drive extracellular matrix (ECM) remodeling to alter tissue environments. The relationship between nutrient deprivation and fibroblast activation remains unclear. Here, we report that serum deprivation extensively activates transcription of ECM remodeling genes in cultured fibroblasts, despite the induction of quiescence. Starvation-induced transcriptional activation accompanied large-scale histone acetylation of putative distal enhancers, but not promoters. The starvation-activated putative enhancers were enriched for non-coding genetic risk variants associated with inflammatory bowel disease (IBD), suggesting that the starvation-activated gene regulatory network may contribute to fibroblast activation in IBD. Indeed, the starvation-activated gene PLAU, encoding uPA serine protease for plasminogen and ECM, was upregulated in inflammatory fibroblasts in the intestines of IBD patients. Furthermore, the starvation-activated putative enhancer at PLAU, which harbors an IBD risk variant, gained chromatin accessibility in IBD patient fibroblasts. This study implicates nutrient deprivation in transcriptional activation of ECM remodeling genes in fibroblasts and suggests nutrient deprivation as a potential mechanism for pathological fibroblast activation in IBD. HIGHLIGHTS- Serum starvation transcriptionally activates ECM remodeling genes in fibroblasts. - Fibroblast starvation activates putative distal enhancers associated with ECM remodeling genes. - Starvation-activated putative enhancers are enriched for inflammatory bowel disease (IBD) risk variants. - PLAU enhancer and expression are activated in IBD intestinal fibroblasts, as in starved fibroblasts.

genomics↗

bioRxiv2024

Cholestasis alters polarization and suppressor function of hepatic regulatory T cells.

Fibrosing cholangiopathies, including biliary atresia and primary sclerosing cholangitis, involve immune-mediated bile duct epithelial injury and hepatic bile acid (BA) retention (cholestasis). Regulatory T-cells (Tregs) can prevent auto-reactive lymphocyte activation, yet the effects of BA on this CD4 lymphocyte subset are unknown. Gene regulatory networks for hepatic CD4 lymphocytes in a murine cholestasis model revealed Tregs are polarized to Th17 during cholestasis. Following bile duct ligation, Stat3 deletion in CD4 lymphocytes preserved hepatic Treg responses. While pharmacological reduction of hepatic BA in MDR2-/- mice prompted Treg expansion and diminished liver injury, this improvement subsided with Treg depletion. A cluster of patients diagnosed with biliary atresia showed both increased hepatic Treg responses and improved 2-year native liver survival, supporting that Tregs might protect against neonatal bile duct obstruction. Together, these findings suggest liver BA determine Treg function and should be considered as a therapeutic target to restore protective hepatic immune responses.

immunology↗