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

•Cardiac deletion of Rhau causes heart defects and embryonic lethality•RHAU associates with both the 5′ and 3′ UTRs of Nkx2-5 mRNA•RHAU resolves the G-quadruplex in Nkx2-5 5′ UTR for effective protein translation•RHAU facilitates HuR-mediated mRNA decay through an AU-rich element in Nkx2-5 3′ UTR

SummaryRNA 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 Rhau leads to heart defects and embryonic lethality in mice. Gene expression profiling identified Nkx2-5 mRNA as a target of RHAU that associates with its 5′ and 3′ UTRs and modulates its stability and translation. The 5′ UTR of Nkx2-5 mRNA contains a G-quadruplex that requires RHAU for protein translation, while the 3′ UTR of Nkx2-5 mRNA possesses an AU-rich element (ARE) that facilitates RHAU-mediated mRNA decay. Thus, we uncovered the mechanisms underlying Nkx2-5 post-transcriptional regulation during heart development. Meanwhile, this study demonstrates the function of mRNA 5′ UTR G-quadruplex-mediated protein translation in organogenesis.

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