N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

N 6-methyladenosine (m 6 A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here we aimed to investigate the role of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a key regulator of m 6 A methylation in gastric cancer (GC) tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m 6 A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of gastric cancer patients and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated GC cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m 6 A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyper-activation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m 6 A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease. Research.

Graphical Abstract Highlights d Single-cell transcriptome profiling constructs lncRNA landscape of HSC development d Computational and functional screening identifies 6 lncRNAs affecting hematopoiesis d Loss of H19 lncRNA results in failed HSC generation from endothelium in AGM region d H19 deficiency leads to promoter hypermethylation of Runx1 and Spi1 in pre-HSCs conceived and supervised the study; J.Z. and L.Z. performed the pre-HSC-and HSC-related experiments with help from J.H. and F.Z.; J.X. performed the bioinformatics analysis with help from X. Wen, Y.M., and Z.L.; S.L. performed shRNA construct and H19 mechanism study with help from Y.M., F.W., X. Wang, and Y.S.; X.L. performed single-cell RNAseq with support from F.T.; Q.L. performed DNA methylation sequencing with support from F.T.; Y.N. performed the flow cytometry with help from P.Z. and C.L.; M.B. provided H19-DMR flDMR/flDMR mice and edited the manuscript; and Y.L., J.Z., J.X., and Y.M. wrote the manuscript with help from J.Y. and B.L.

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MicroRNA (miRNA) biogenesis is finely controlled by complex layers of post-transcriptional regulators, including RNA-binding proteins (RBPs). Here, we show that an RBP, QKI5, activates the processing of primary miR-124-1 (pri-124-1) during erythropoiesis. QKI5 recognizes a distal QKI response element and recruits Microprocessor through interaction with DGCR8. Furthermore, the recruited Microprocessor is brought to pri-124-1 stem loops by a spatial RNA-RNA interaction between two complementary sequences. Thus, mutations disrupting their base-pairing affect the strength of QKI5 activation. When erythropoiesis proceeds, the concomitant decrease of QKI5 releases Microprocessor from pri-124-1 and reduces mature miR-124 levels to facilitate erythrocyte maturation. Mechanistically, miR-124 targets TAL1 and c-MYB, two transcription factors involved in normal erythropoiesis. Importantly, this QKI5-mediated regulation also gives rise to a unique miRNA signature, which is required for erythroid differentiation. Taken together, these results demonstrate the pivotal role of QKI5 in primary miRNA processing during erythropoiesis and provide new insights into how a distal element on primary transcripts affects miRNA biogenesis.