Identification of a LncRNA EPR—>METTL7A1 pathway modulating translation of select genes (Polysomes)

EPR is a long non-coding RNA (lncRNA) that controls cell proliferation in mammary gland cells by regulating gene transcription and, here, we report on Mettl7a1 as a target of EPR. We show that the lncRNA induces Mettl7a1 transcription by remodeling the 3-dimensional chromatin structure at the Mettl7a1 locus. Our data indicate that METTL7A1 participates in the EPR-dependent pathway that antagonizes TGF-β signaling. METTL7A1 is absent in tumorigenic murine mammary gland cells and its human ortholog (METT7A) is downregulated in breast cancers. Importantly, expression of METTL7A1 in 4T1 tumorigenic cells reduces their transformation potential, and the putative methyltransferase activity of METTL7A1 appears dispensable for its biological functions. METTL7A1 is a cytoplasmic protein and, from a mechanistic perspective, interacts with factors implicated in the early steps of mRNA translation, associates with ribosomes, and affects the levels of select proteins without substantial changes in mRNA abundance. Our data suggest the possibility that METTL7A1 conveys the transcriptional regulation operated by EPR into specific changes of mRNA translation. Polysomal and sub-polysomal RNA isolated upon sucrose gradient centrifugation from Mock and Mettl7a1 4T1 transfected cells. RNA was equenced in triplicates 12 samples.