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The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition

ABSTRACT: The functional consequence of N6-methyladenosine (m6A) RNA modification is mediated by ‘reader’ proteins like those of the YTH family that recruit additional factors to alter splicing, RNA stability or translation. Germline-specific YTH domain-containing 2 (YTHDC2) is essential for mammalian fertility, but its molecular function is poorly understood. Here we use a tagged mouse line to identify U-rich motifs as binding sites of YTHDC2 on 3′ UTRs of testicular RNA targets. Although its YTH domain is an m6A-binder in vitro, the YTH point mutant mouse lacking this ability displays no obvious phenotypes. Its 3′→5′ RNA helicase activity is essential for fertility, with the catalytic-dead mutation being dominant-negative. Single-cell transcriptomics reveal that Ythdc2 mutant mitotic testicular germ cells transition into meiosis but accumulate a transcriptome with mixed mitotic/meiotic identity. We also reveal a conserved role for YTHDC2 in animal fertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE196427 | GEO | 2022/03/22

REPOSITORIES: GEO

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Regulation of m6A transcripts by the 3ʹ→5ʹ RNA helicase YTHDC2 is essential for a successful meiotic program in the mammalian germline

Project description:N6-methyladenosine (m6A) is an essential internal RNA modification that is critical for gene expression control in most organisms. Proteins with a YTH domain recognize m6A marks and are mediators of molecular functions like RNA splicing, mRNA decay and translation control. Here we demonstrate that YTH domain-containing 2 (YTHDC2) is an m6A reader that is essential for male and female fertility in mice. In mutant males, mitotic spermatogonia fail to differentiate into meiotic spermatocytes. Analysis identifies transcripts upregulated in the Yhtdc2 mutant testes to be those that are expressed in purified spermatogonia, while high-throughput mapping of the m6A transcriptome in the mouse male germline demonstrates the upregulated transcripts to be those that are enriched in m6A marks. Our biochemical studies indicate that YTHDC2 is an RNAinduced ATPase that fuels its 3ʹ→5ʹ RNA helicase activity. Interestingly, we find an RNA-independent interaction between the 5ʹ→3ʹ exoribonuclease XRN1 and the Ankyrin repeat of YTHDC2 that is wedged in between the two RecA helicase domains. Our studies reveal a role for YTHDC2 in modulating the levels of m6A-modified germline transcripts that is essential for successful meiosis.

2017-10-14 | GSE102346 | GEO

YTHDC2 regulates spermatogenesis through promoting the translation of N6-methyladenosine-modified RNA

Project description:N6-methyladenosine (m6A) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as an essential layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. m6A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to promote the translation of m6A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the splicing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds m6A along its consensus motif GGACU. YTHDC2 promotes translation of its targets, and associates with cellular fractions involved in translation initiation. Ythdc2 knockout mice are infertile and have significantly smaller testes compared to those of littermates. In the testes, Ythdc2 is temporally expressed as meiosis begins, and germ cells of Ythdc2 knockout mice do not develop past the spermatogonium stage. Thus, YTHDC2 is an m6A binding protein that plays essential roles in spermatogenesis.

2017-08-01 | GSE98085 | GEO

Structural basis of YTH domain as m6A reader

Project description:The N6-methyladenosine (m6A) is the most abundant internal modification in almost all eukaryotic messenger RNAs, and is dynamically regulated. Therefore, identification of m6A readers is especially important in determining the cellular function of m6A. YTHDF2 has recently been characterized as the first m6A reader that regulates the cytoplasmic stability of methylated RNA. Here we show that YTHDC1 is a nuclear m6A reader and report the crystal structure of the YTH domain of YTHDC1 bound to m6A-containing RNA. We further determined the structure of another YTH domain, YTHDF1, and found that the YTH domain utilizes a conserved aromatic cage to specifically recognize the methyl group of m6A. Our structural characterizations of the YTHDC1-m6A RNA complex also shed light on the molecular basis for the preferential binding of the GG(m6A)C sequence by YTHDC1 and confirm the YTH domain as a specific m6A RNA reader. PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) was applied to human YTHDC1 protein to identify its binding sites.

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Regulation of the transition from mitosis to meiosis by the conserved RNA-helicase YTHDC2/BGCN [RIP-Seq]

Project description:In the germline stem cell lineage, proliferating gonial cells switch from mitotic proliferation to meiotic prophase, marked by the onset of a cell-type-specific transcription program and a specialized cell cycle required to generate haploid gametes. The Drosophila gene benign gonial cell neoplasm (bgcn) encodes an RNA binding translational repressor required in fly testes for spermatogonia to stop dividing and transition to the spermatocyte state and meiosis. Here we show that the mammalian bgcn ortholog, YTHDC2, plays a key role in allowing a clean transition from mitosis to meiosis in both male and female germ cells in mouse, pointing towards a conserved role of post-transcriptional control of RNA translation and/or stability in this critical cell fate transition. Ythdc2-/- male germ cells undergo mitotic divisions but fail to properly execute meiotic prophase, instead attempting a mitotic-like division then undergoing cell death. Many meiotic markers were only weakly expressed in Ythdc2-/- testes compared to wild-type controls. Strikingly, the mitotic cyclin Cyclin A2, which is down-regulated prior to entry into meiotic prophase in wild-type, remained high in Ythdc2-/- germ cells that also expressed the meiotic marker SYCP3, suggesting that the mutant germ cells attempting to enter meiotic prophase have a mixed identity. YTHDC2 binds RNAs involved in both the mitotic cell cycle, including the mRNA Ccna2 that encodes Cyclin A2, as well as specific piRNA precursor RNAs and transcripts required for later stages of germ cell differentiation. YTHDC2-bound RNAs in testes were enriched for the m6A modification, suggesting that YTHDC2 may selectively regulate multiple target RNAs marked with m6A, to promote a clean transition from mitosis to meiosis and terminal differentiation.

2017-11-15 | GSE93533 | GEO

Regulation of the transition from mitosis to meiosis by the conserved RNA-helicase YTHDC2/BGCN [RNA-Seq]

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Project description:Mechanisms regulating mammalian meiotic progression are poorly understood. Here we identify mouse YTHDC2 as a critical component. A screen yielded a sterile mutant, “ketu”, caused by a Ythdc2 missense mutation. Mutant germ cells enter meiosis but proceed prematurely to aberrant metaphase and apoptosis, and display defects in transitioning from spermatogonial to meiotic gene expression programs. ketu phenocopies mutants lacking MEIOC, a YTHDC2 partner. Consistent with roles in post-transcriptional regulation, YTHDC2 is cytoplasmic, has 3’ to 5’ RNA helicase activity in vitro, and has similarity within its YTH domain to an N6-methyladenosine recognition pocket. Orthologs are present throughout metazoans, but are diverged in nematodes and, more dramatically, Drosophilidae, where Bgcn is descended from a Ythdc2 gene duplication. We also uncover similarity between MEIOC and Bam, a Bgcn partner unique to schizophoran flies. We propose that regulation of gene expression by YTHDC2-MEIOC is an evolutionarily ancient strategy for controlling the germline transition into meiosis.

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The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition

Project description:The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition

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Project description:YTHDC2 CLIP

| PRJNA789249 | ENA

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