The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

Abstract 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.</jats:p

Supplementary Materials and Methods from YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of &lt;i&gt;FZD7&lt;/i&gt;

&lt;p&gt;Supplementary Materials and Methods&lt;/p&gt;</jats:p

Supplementary Table S3 from YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of &lt;i&gt;FZD7&lt;/i&gt;

&lt;p&gt;The mutation information of m6A peaks on FZD7. Related to Figure 5.&lt;/p&gt;</jats:p

Supplementary Table S5 from YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of &lt;i&gt;FZD7&lt;/i&gt;

&lt;p&gt;Association between YTHDF1 levels in gastric cancer and clinical findings. Related to Figure 1.&lt;/p&gt;</jats:p

YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of <i>FZD7</i>

Abstract N6-methyladenosine (m6A) 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 m6A RNA-binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated gastric cancer cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease. Significance: This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment. </jats:sec

The RNA-binding protein QKI5 regulates primary miR-124-1 processing via a distal RNA motif during erythropoiesis

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-1241 (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.National Key Research and Development Program of China [2016YFA0100601]; National Key Basic Research Program of China [2015CB94300]; National Natural Science Foundation of China [81530007, 9144011, 31371322, 31471227]; CAMS Initiative for Innovative Medicine [2016-12M-3-002]SCI(E)ARTICLE3416-4392

A Chromosome-Scale Genome Assembly of Paper Mulberry (Broussonetia papyrifera) Provides New Insights into Its Forage and Papermaking Usage

Paper mulberry (Broussonetia papyrifera) is a well-known woody tree historically used for Cai Lun papermaking, one of the four great inventions of ancient China. More recently, Paper mulberry has also been used as forage to address the shortage of feedstuff because of its digestible crude fiber and high protein contents. In this study, we obtained a chromosome-scale genome assembly for Paper mulberry using integrated approaches, including Illumine and PacBio sequencing platform as well as Hi-C, optical, and genetic maps. The assembled Paper mulberry genome consists of 386.83 Mb, which is close to the estimated size, and 99.25% (383.93 Mb) of the assembly was assigned to 13 pseudochromosomes. Comparative genomic analysis revealed the expansion and contraction in the flavonoid and lignin biosynthetic gene families, respectively, accounting for the enhanced flavonoid and decreased lignin biosynthesis in Paper mulberry. Moreover, the increased ratio of syringyl-lignin to guaiacyl-lignin in Paper mulberry underscores its suitability for use in medicine, forage, papermaking, and barkcloth making. We also identified the root-associated microbiota of Paper mulberry and found that Pseudomonas and Rhizobia were enriched in its roots and may provide the source of nitrogen for its stems and leaves via symbiotic nitrogen fixation. Collectively, these results suggest that Paper mulberry might have undergone adaptive evolution and recruited nitrogen-fixing microbes to promote growth by enhancing flavonoid production and altering lignin monomer composition. Our study provides significant insights into genetic basis of the usefulness of Paper mulberry in papermaking and barkcloth making, and as forage. These insights will facilitate further domestication and selection as well as industrial utilization of Paper mulberry worldwide

Supplementary Figure S6 from YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of &lt;i&gt;FZD7&lt;/i&gt;

&lt;p&gt;YTHDF1~FZD7~β-catenin axis promotes gastric cancer progression.&lt;/p&gt;</jats:p

Supplementary Table S7 from YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of &lt;i&gt;FZD7&lt;/i&gt;

&lt;p&gt;Identification of YTHDF1-regulated transcripts by RNA-seq, RIP-seq and MeRIP-seq. Related to Figure 3. This file contains six tabs: 1, RNA profiling revealed transcripts that were dysregulated upon YTHDF1 deficiency. 2, YTHDF1-binding genes revealed by RIP-seq within MGC-803 cells. 3, m6A peaks revealed by m6A-seq within MGC-803 cells. 4, The overlap of transcripts identified by YTHDF1 specific RIP-seq and MeRIP-seq. 5, The overlap of transcripts were enriched in Wnt and Hippo signaling pathways. 6, YTHDF1 candidate targets in the Hippo or Wnt pathways.&lt;/p&gt;</jats:p

Supplementary Table S2 from YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of &lt;i&gt;FZD7&lt;/i&gt;

&lt;p&gt;Primers used in this study. Related to Figure 4, Figure5 and Figure6.&lt;/p&gt;</jats:p