
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.06.611754
preprint
1
Article
Nutrient starvation activates ECM remodeling gene enhancers associated with inflammatory bowel disease risk in fibroblasts
Secchia Stefano
Beilinson Vera
Chen Xiaoting
Yang Zi F.
Wayman Joseph A.
Dhaliwal Jasbir
Jurickova Ingrid
Angerman Elizabeth
Denson Lee A.
Miraldi Emily R.
Weirauch Matthew T.
Ikegami Kohta http://orcid.org/0000-0002-0405-1193

12 9 2024
2024.09.06.611754https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.06.611754
nihpp-2024.09.06.611754.pdf
ABSTRACT

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.
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