Post-transcriptional Regulation of Nkx2-5by RHAU in Heart Development

RNA G-quadruplexes (G4s) play important roles in RNA biology. However, the function and regulation of mRNA G-quadruplexes in embryonic development remain elusive. Previously, we identified RHAU (DHX36, G4R1) as an RNA helicase that resolves mRNA G-quadruplexes. Here, we find that cardiac deletion of Rhauleads to heart defects and embryonic lethality in mice. Gene expression profiling identified Nkx2-5mRNA as a target of RHAU that associates with its 5′ and 3′ UTRs and modulates its stability and translation. The 5′ UTR of Nkx2-5mRNA contains a G-quadruplex that requires RHAU for protein translation, while the 3′ UTR of Nkx2-5mRNA possesses an AU-rich element (ARE) that facilitates RHAU-mediated mRNA decay. Thus, we uncovered the mechanisms underlying Nkx2-5post-transcriptional regulation during heart development. Meanwhile, this study demonstrates the function of mRNA 5′ UTR G-quadruplex-mediated protein translation in organogenesis.