Secchia Stefano, Beilinson Vera, Chen Xiaoting, Gucwa Melanie, Denson Lee A, Miraldi Emily R, Weirauch Matthew T, Ikegami Kohta
Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA; Department of Biology, Lund University, 22362 Lund, Sweden.
Department of Pediatrics, The University of Chicago, Chicago, IL 60637, USA.
Cell Rep. 2025 Jul 22;44(7):115896. doi: 10.1016/j.celrep.2025.115896. Epub 2025 Jun 24.
Depletion of growth factors and nutrients induces cellular quiescence, which often accompanies transcriptional silencing and chromatin compaction. Paradoxically, such depletion occurs in pathological microenvironments in which fibroblasts are activated to orchestrate tissue remodeling. The relationship between fibroblast activation and growth factor and nutrient depletion remains unclear. Here, we report that serum depletion in cell culture, a model for growth factor and nutrient depletions, extensively activates transcription in fibroblasts despite inducing quiescence. Activated genes were enriched for extracellular matrix (ECM) structural components and proteases. ECM-related transcription accompanied the activation of putative distal enhancers but not promoters. The activated putative enhancers were enriched for non-coding variants associated with inflammatory bowel disease (IBD) risk, suggesting an alteration in the ECM-remodeling gene regulatory network in IBD. This study implicates nutrient and growth factor depletion in activating the ECM-remodeling gene program in fibroblasts, challenging the prevailing view linking such depletion to transcriptional dormancy.
生长因子和营养物质的耗尽会诱导细胞静止，这通常伴随着转录沉默和染色质压缩。矛盾的是，这种耗尽发生在病理微环境中，在这种环境中，成纤维细胞被激活以协调组织重塑。成纤维细胞激活与生长因子和营养物质耗尽之间的关系仍不清楚。在这里，我们报告细胞培养中的血清耗尽，一种生长因子和营养物质耗尽的模型，尽管诱导静止，但仍广泛激活成纤维细胞中的转录。激活的基因富含细胞外基质（ECM）结构成分和蛋白酶。ECM相关转录伴随着假定的远端增强子而非启动子的激活。激活的假定增强子富含与炎症性肠病（IBD）风险相关的非编码变体，表明IBD中ECM重塑基因调控网络发生了改变。这项研究表明营养物质和生长因子耗尽会激活成纤维细胞中的ECM重塑基因程序，挑战了将这种耗尽与转录休眠联系起来的主流观点。
