Inhibition of ACSS2-mediated H3K9 crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence

Abstract

Abstract Histone lysine crotonylation (Kcr), a novel posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown. In this study, we report that histone Kcr of tubular epithelial cells was significantly elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme—ACSS2 (acyl-CoA synthetase short chain family member 2)—was found to remarkably promote histone 3 lysine 9 crotonylation (H3K9cr) without influencing H3K9ac. Combined analysis of ChIP and RNA sequencing revealed that the hub proinflammatory cytokine, IL-1β (which is regulated by H3K9cr), may play a significant role in kidney fibrosis. Genetic and pharmacologic inhibition of ACSS2 both attenuated kidney fibrosis, as well as suppressed H3K9cr-mediated IL-1β expression, which thereby alleviated IL-1β-dependent macrophage activation and tubular cell senescence. Collectively, our findings uncover that H3K9cr plays a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive target for strategies that aim to slow fibrotic kidney disease progression.