YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths

Abstract

N⁶-methyladenosine (m⁶A) is a critical regulator in the fate of RNA, but whether and how m⁶A executes its functions in different tissues remains largely obscure. Here we report downregulation of a crucial m⁶A reader, YTHDF2, leading to tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, Bisphenol A (BPA) substitutes are widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m⁶A-<i>gch1</i> for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m⁶A-<i>sting1</i> decay for caudal vein plexus (CVP) apoptosis. The two distinct YTHDF2-mediated m⁶A regulations and context-dependent co-expression patterns of <i>gch1/ythdf2</i> and <i>tnfrsf1a/ythdf2</i> contributed to YTHDF2-mediated tissue-specific PCDs, uncovering a new layer of PCD regulation. Since BHPF/YTHDF2-medaited PCD defects were also observed in mammals, BHPF exposure represents a potential health threat.