m⁶A methylation inhibits recruitment of the Dand5 3′UTR to the left–right determinant Bicc1

Abstract

In vertebrates, left–right (LR) asymmetry is specified by asymmetric decay of Dand5 messenger RNA (mRNA) mediated by the recruitment of the BicC family RNA binding protein 1 (Bicc1). Besides regulating organ laterality, Bicc1 is required to prevent cystic dilations in renal tubules and in pancreatic and bile ducts. However, validated target mRNAs are sparse in number, and how their binding to Bicc1 is regulated remains poorly understood. Bicc1 recruitment to Dand5 transcripts requires a conserved AGACGUGAC motif in the 3′UTR. Here, we report an N⁶-methyladenosine (m⁶A) in this sequence that disrupts binding to Bicc1 K homology (KH) domains in vitro, in stark contrast to IGF2BPs and FMR1, where m⁶A promotes RNA recognition by KH domains. We discuss the possible implications of this finding for LR axis formation and for a related role of Bicc1 in regulating specific target mRNAs in the kidney.