YY1 Lactylation Aggravates Autoimmune Uveitis by Enhancing Microglial Functions via Inflammatory Genes

Abstract

Activated microglia in the retina are essential for the development of autoimmune uveitis. Yin‐Yang 1 (YY1) is an important transcription factor that participates in multiple inflammatory and immune‐mediated diseases. Here, an increased YY1 lactylation in retinal microglia within in the experimental autoimmune uveitis (EAU) group is observed. YY1 lactylation contributed to boosting microglial activation and promoting their proliferation and migration abilities. Inhibition of lactylation suppressed microglial activation and attenuated inflammation in EAU. Mechanistically, cleavage under targets & tagmentation （CUT&Tag） analysis revealed that YY1 lactylation promoted microglial activation by regulating the transcription of a set of inflammatory genes, including STAT3, CCL5, IRF1, IDO1, and SEMA4D. In addition, p300 is identified as the writer of YY1 lactylation. Inhibition of p300 decreased YY1 lactylation and suppressed microglial inflammation in vivo and in vitro. Collectively, the results showed that YY1 lactylation promoted microglial dysfunction in autoimmune uveitis by upregulating inflammatory cytokine secretion and boosting cell migration and proliferation. Therapeutic effects can be achieved by targeting the lactate/p300/YY1 lactylation/inflammatory genes axis.

A feedback loop driven by H3K9 lactylation and HDAC2 in endothelial cells regulates VEGF-induced angiogenesis

“…Lactylation is a new method to transduce cellular metabolic characteristics into gene expression programs. Our studies and others have reported that lactylation can influence protein function and participate in multiple physiological and pathological processes [ 17 – 21 ]. The lactylation of H3K18 promotes the transcription of YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2), which is involved in ocular melanoma [ 22 ].…”

“…As previous studies reported, histones play important roles in modulating chromatin structure and function, including transcriptional regulation [ 14 , 15 ]. Post-translational modifications could influence histone’s binding to the promoters of specific genes and then regulates gene transcription [ 20 , 21 ]. We found that hyperlactylation of H3K9 inhibited its interaction with HDAC2, and this process is reversed in response to glycolysis inhibitor treatment.…”