Trimethylamine disturbs chromatin accessibility to block ferroptosis and promotes tumorigenesis[Chip-seq]
In this study, we found that FMO3 was depleted in advanced HCC cells and overexpression of FMO3 would drive ferroptosis. However, Both Trimetlylamine oxide (TMAO), a metabolite of FMO3, and its substrate Trimethylamine (TMA), inhibit ferroptosis of HCC cells. Mechanically, FGF signals for ALKBH5 phosphorylation at Y139 and then impairs ALKBH5 targeting FMO3 mRNA, upregulating FMO3 expression. Meanwhile, TMA competitively binds and inhibits the recognition of H3K4me3 by chromodomain in CHD1, which is responsible for shaping the accessible chromatin at the ACLS4 promoter. In turn, excessive product TMAO blocks FMO3 activity to prevent the conversion of TMA in chromodomain into TMAO, consequently, TMAO also prevents chromodomain to recognize H3K4me3. Structurally, we resolved the targeting mode of TMA in chromodomain, and CHD1 protein with TMA in chromo domain was deprived of the ability recognizing H3K4me3. Thus, TMA disturbs chromatin accessibility and promotes ferroptosis by driving ACSL4 expression. ALKBH5/FMO3/CHD1 axis also showed clinical significance and high TMA/TMAO in blood would be a beneficial indicator for anti-vascular treatment.