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The RNA m6A binding protein YTHDF2 promotes the B cell to plasma cell transition

ABSTRACT: The B cell to plasma cell transition relies on the coordinated remodelling of the gene expression program. We performed a CRISPR/Cas9 knockout screen of RNA binding proteins to identify post-transcriptional regulation of gene expression during the B cell terminal differentiation. The m6A binding protein YTHDF2 was identified as promoting B cell terminal differentiation. In the absence of YTHDF2 the germinal centre reaction is broadly intact, however, plasma cells fail to accumulate. YTHDF2 has previously been shown to mediate RNA decay through the recruitment of the CCR4-NOT deadenylase machinery. Furthermore, our genetic screen in B cells identified that other CCR4-NOT recruitment factors inhibit rather than promote differentiation. Thus, the CCR4-NOT complex coordinates competing regulatory pathways of B cell differentiation at the post-transcriptional level.

ORGANISM(S): Mus musculus

PROVIDER: GSE179919 | GEO | 2021/07/13

REPOSITORIES: GEO

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YTHDF2/3 are required for somatic reprogramming through different RNA deadenylation pathways

Project description:N6-methyladenosine (m6A), the most abundant reversible modification on eukaryote messenger RNA, is recognized by a series of readers, including the YT521-B homology domain family (YTHDF) proteins, which are coupled to perform physiological functions. Here, we report that YTHDF2 and YTHDF3, but not YTHDF1, are required for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). Mechanistically, we found that YTHDF3 recruits the PAN2-PAN3 deadenylase complex and conduces to reprogramming by promoting mRNA clearance of somatic genes, including Tead2 and Tgfb1, which parallels the activity of the YTHDF2-CCR4-NOT deadenylase complex. Ythdf2/3 deficiency further represses mesenchymal-to-epithelial transition (MET) and chromatin silencing at loci containing the TEAD motif, contributing to decreased reprogramming efficiency. Moreover, RNA interference of Tgfb1 or the Hippo signaling effectors Yap1, Taz, and Tead2 rescues Ythdf2/3-defective reprogramming. Overall, YTHDF2/3 couple RNA deadenylation and regulation with the clearance of somatic genes provides insights into iPSC reprogramming at the posttranscriptional level.

2020-08-19 | GSE156437 | GEO

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The RNA m6A reader YTHDF2 controls NK cell anti-tumor and anti-viral immunity

Project description:N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification on RNA. NK cells are the predominant innate lymphoid cells that mediate anti-viral and anti-tumor immunity. However, whether and how m6A modifications affect NK cell immunity remains unknown. Here, we discover that YTHDF2, a well-known m6A reader, is upregulated in NK cells upon activation by cytokines, tumors, and cytomegalovirus infection. Ythdf2 deficiency in NK cells impairs NK cell anti-tumor and anti-viral activity in vivo. YTHDF2 maintains NK cell homeostasis and terminal maturation, correlating with modulating NK cell trafficking and regulating Eomes, respectively. YTHDF2 promotes NK cell effector function and is required for IL-15-mediated NK cell survival and proliferation by forming a STAT5-YTHDF2 positive feedback loop. Transcriptome-wide screening identifies Tardbp to be involved in cell proliferation or survival as a YTHDF2-binding target in NK cells. Collectively, we elucidate the biological roles of m6A modifications in NK cells and highlight a new direction to harness NK cell anti-tumor immunity.

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Microarray analysis of YTHDF2-deficient leukemic stem cells

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YTHDF2 inhibition potentiates radiotherapy by reprogramming suppressive myeloid cells [scRNA-Seq]

Project description:RNA N6-methyladenosine (m6A) modification is implicated in cancer progression. However, the impact of m6A on the antitumor effects of radiotherapy and the related mechanisms are unknown. Here we show that ionizing radiation (IR) induces immunosuppressive myeloid-derived suppressor cell (MDSC) expansion and YTHDF2 expression in both murine models and humans. Following IR, loss of Ythdf2 in myeloid cells augments antitumor immunity and overcomes tumor radioresistance by altering MDSC differentiation and inhibiting MDSC infiltration and suppressive function. The remodeling of the landscape of MDSC populations by local IR is reversed by Ythdf2 deficiency. IR-induced YTHDF2 expression relies on NF-κB signaling; YTHDF2 in turn leads to NF-κB activation by directly binding and degrading transcripts encoding negative regulators of NF-κB signaling, resulting in an IR-YTHDF2-NF-κB circuit. Pharmacological inhibition of YTHDF2 overcomes MDSC-induced immunosuppression and improves combined IR and/or anti-PD-L1 treatment. Thus, YTHDF2 is a promising target to improve radiotherapy (RT) and RT/immunotherapy combinations.

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YTHDF2 inhibition potentiates radiotherapy by reprogramming suppressive myeloid cells [MeRIP-Seq]

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YTHDF2 inhibition potentiates radiotherapy by reprogramming suppressive myeloid cells [CITE-Seq]

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YTHDF2 inhibition potentiates radiotherapy by reprogramming suppressive myeloid cells [RIP-Seq]

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Ythdf2-mediated m6A mRNA clearance modulates neural development in mice

Project description:We found that the proliferation and differentiation capabilities of NSPCs decrease significantly in Ythdf2 null mutants.To explore the underlying molecular mechanism, we performed transcriptomics and well-established m6A-methylome analyses of NSPCs dervied from wild type and Ythdf2-/- embryo brains. RNA-seq data revealed that expressions of genes enriched in neural development pathways were significantly disturbed. The inhibitory genes, like Flrt2, Ptprd, et al. in regulation of JAK-STAT cascade, which contributes to the neuroprotection and neurite outgrowth, showed increased gene expressions and m6A enrichment by m6A-seq. We identified that without the recognizing and binding of Ythdf2, the degradation of neuron differentiation related m6A-modified mRNAs were delayed in Ythdf2-/-, thereby disturbing the proliferation and differentiation of NSPCs. In summary, our findings uncovered that Ythdf2 modulates neural developmental via regulating the clearance of mRNA targets.

2018-01-01 | GSE104867 | GEO

YTHDF2 suppresses the plasmablast genetic program and promotes germinal center formation

Project description:Antibody-mediated immunity is initiated by B cell interactions with cognate antigen, followed by differentiation into multiple cell subsets, including plasmablast, memory, and germinal center (GC) cells. B cell differentiation trajectories are determined by specific transcription factors, yet very few mechanisms that determine B cell fate at the early stage of the response have been described. Here, we report an epigenetic mechanism that specifically suppresses the plasmablast genetic program and promotes GC B cell fate commitment. Single-cell RNA-seq analysis of antigen-specific B cells revealed activated B cell precursors at the pre-GC stage that express high levels of RNA binding proteins, including YTHDF2, which enhances the decay of methylated transcripts. Ythdf2-deficient B cells exhibited intact proliferation and upregulation of early activation markers in response to antigenic stimulation, whereas differentiation into GC B cells was blocked. Mechanistically, B cells required YTHDF2 to attenuate the plasmablast genetic program during GC seeding, and key transcripts of plasmablast-related genes, including Irf4 and Xbp1, were methylated and bound by YTHDF2. Modulation of YTHDF2-dependent gene expression by YTHDF1 and YTHDF3 was less pronounced, and no functional redundancy of these paralogs in GC seeding was observed. Collectively, this study reveals a novel epigenetic mechanism that specifically directs appropriate B cell fate commitment through post-transcriptional suppression of gene expression.

2022-04-24 | GSE189819 | GEO

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