Abstract
In eukaryotes,RNA N6-methyladenosine(m6A)modification and microRNA(miRNA)-mediated RNA silencing represent two critical epigenetic regulatory mechanisms.The m6A methyl-transferase complex(MTC)and the micro-processor complex both undergo liquid-liquid phase separation to form nuclear membraneless organelles.Although m6A methyltransferase has been shown to positively regulate miRNA biogenesis,a mechanism of reciprocal regu-lation between the MTC and the microprocessor complex has remained elusive.Here,we demonstrate that the MTC and the micro-processor complex associate with each other through the METHYLTRANSFERASE B(MTB)-SERRATE(SE)interacting module.Knockdown of MTB impaired miRNA biogenesis by diminishing microprocessor complex binding to primary miRNAs(pri-miRNAs)and their re-spective MIRNA loci.Additionally,loss of SE function led to disruptions in transcriptome-wide m6A modification.Further biochemical assays and fluorescence recovery after photobleaching(FRAP)assay indicated that SE enhances the liquid-liquid phase separation and solubility of the MTC.Moreover,the MTC exhibited en-hanced retention on chromatin and diminished binding to its RNA substrates in the se mutant background.Collectively,our results reveal the substantial regulatory interplay between RNA m6A modification and miRNA biogenesis.