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YTHDF2 contributes to psoriasis by promoting proliferation and inflammatory response through regulation of Wnt signaling pathway

ABSTRACT: YT521-B homology domain family 2 (YTHDF2), an m6A-binding protein, plays a crucial role in various biological processes, including cell migration, proliferation, differentiation, and inflammation. It is also involved in mRNA decay and pre-rRNA processing. This study investigates the specific impact of YTHDF2 on the pathogenesis of psoriasis and its underlying mechanisms. Initially, increased expression of YTHDF2 was observed in psoriasis. Subsequent silencing of YTHDF2 in psoriatic cell model led to a decrease in mRNA expression of IL-17A, S100A8, and S100A9, as well as a reduction in cell proliferation. Conversely, overexpression of YTHDF2 resulted in the opposite effects. Treatment with the YTHDF2 inhibitor DC-Y27-13 demonstrated a therapeutic effect on psoriasis mice. mRNA sequencing analysis revealed enrichment of differentially expressed genes in the Wnt signaling pathway. Further investigation indicated that deletion of YTHDF2 increased the half-life and expression of Dickkopf homolog 3 (DKK3), which in turn inhibited the Wnt signaling pathway, ultimately attenuating the inflammatory response and inhibiting cell proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272325 | GEO | 2024/12/13

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

RNA-seq analysis of dickkopf-3 knockout and C57Bl/6 mice kidneys 7 days after unilateral ureteral obstruction

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RNA m6A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/ β-catenin signaling

Project description:Lung cancer is a leading cause of cancer-related mortality worldwide and poor prognosis remains a major problem encountered in its treatment. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has been recently implicated in the tumorigenesis and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of YTHDF2 in the regulation of lung adenocarcinoma (LUAD) progression remain elusive. Here we report that YTHDF2 expression was significantly increased in lung adenocarcinoma than in adjacent normal tissues. YTHDF2 knockdown drastically inhibited cell proliferation, colony formation, and migration in vitro, and the opposite proved true when YTHDF2 was overexpressed. In addition, YTHDF2 attenuation significantly inhibited tumorigenesis in a murine tumor xenograft model. Through the integrative analysis of RNA-seq, m6A-seq, CLIP-seq, and RIP-seq datasets, we identified a set of potential direct targets of YTHDF2 in lung adenocarcinoma. We further confirmed AXIN1, which encodes a negative regulator of the Wnt/β-catenin signaling, as a direct target of YTHDF2. YTHDF2 promotes AXIN1 RNA decay and subsequently activates the Wnt/β-catenin signaling. Knockout of AXIN1 can sufficiently rescue the inhibitory effect of YTHDF2 depletion on lung cancer cell proliferation, colony-formation, and migration. Collectively, our results uncovered YTHDF2-mediated regulation of the AXIN1/Wnt/β-catenin signaling that contributes to LUAD tumorigenesis, and thus provided insight into the mechanisms underlying lung adenocarcinoma progression.

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YTHDF2 contributes to psoriasis by promoting proliferation and inflammatory response through regulation of Wnt signaling pathway

Project description:YTHDF2 contributes to psoriasis by promoting proliferation and inflammatory response through regulation of Wnt signaling pathway

| PRJNA1136457 | ENA

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.

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Dickkopf 3 Promotes the Differentiation of Substantia Nigra Dopaminergic Neurons In Vivo and from Pluripotent Stem Cells In Vitro

Project description:WNT1/beta-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons including the Substantia nigra pars compacta (SNc) subpopulation, whose degeneration is a hallmark of Parkinson’s Disease (PD). However, the precise functions of WNT/beta-catenin signaling in this context remain unknown. Using mutant mice, primary ventral midbrain (VM) cells and pluripotent stem cells (mouse embryonic stem cells and induced pluripotent stem cells), we show that Dickkopf 3 (DKK3), a secreted glycoprotein that modulates WNT/beta-catenin signaling, is specifically required for the correct differentiation of a rostrolateral mdDA precursor subset into SNc DA neurons. Dkk3 transcription in the murine VM coincides with the onset of mdDA neurogenesis and is required for the maintenance of LMX1A and consequently PITX3 expression in rostrolateral mdDA precursors, without affecting the proliferation or specification of their progenitors. Treatment of primary VM cells or differentiating pluripotent stem cells with recombinant WNT1 and/or DKK3 proteins consistently increases the proportion of mdDA cells with SNc DA neuron identity and promotes their survival in vitro. The SNc DA pro-differentiation and pro-survival properties of DKK3, together with its known anti-tumorigenic effect, therefore make it an ideal candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD. We performed gene expression microarray analysis on iPSC-derived and FACS-sorted GFP-positive Pitx3GFP/+ mdDA neurons, differentiated in the presence or absence of recombinant human WNT1 and recombinant human DKK3. In addition, we analysed primary and FACS-sorted GFP-positive Pitx3+/GFP mdDA neurons isolated from the E13.5 and E14.5 ventral midbrain of Pitx3+/GFP embryos

2015-08-22 | E-GEOD-58813 | biostudies-arrayexpress

Dickkopf 3 Promotes the Differentiation of Substantia Nigra Dopaminergic Neurons In Vivo and from Pluripotent Stem Cells In Vitro

2015-08-22 | GSE58813 | GEO

SLAM-Seq analysis of Ythdf2-deficient pre-leukemic cells

Project description:The mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human acute myeloid leukemias (AML). To study the role of YTHDF2 on mRNA decay rates in leukemia, c-Kit+ cells from foetal livers of Ythdf2fl/fl; Vav-iCre (Ythdf2CKO) and Ythdf2fl/fl (Ythdf2CTL) 14.5 dpc embryos were transduced with Meis1 and Hoxa9 oncogenes and serially re-plated to generate pre-leukemic cells. Medium with 4SU was used for pre-leukemic cells labelling for 12 hours and was later replaced with 4SU-free medium (time 0). Cells were collected immediately after medium change and at 1, 3 and 9 hours for library generation. RNA from Ythdf2CKO (n=3 biological replicates) and Ythdf2CTL (n=3 biological replicates) pre-leukemic cells were used for SLAM-seq library generation.

2019-04-05 | E-MTAB-7784 | biostudies-arrayexpress

YTHDF2 irCLIP-seq

Project description:We performed irCLIP-seq to determine the mRNA targets of YTHDF2 in mouse hematopoietic progenitor cell line HPC-7

2018-08-17 | GSE107953 | GEO

Microarray profiling of YTHDF2 deficient mouse oocytes

Project description:To study the role of the protein YTHDF2 during female gametogenesis, its gene was conditionally deleted in oocytes. Total RNA samples from YTHDF2 deficient GV and MII oocytes (and control oocytes) were subjected to array profiling.

2018-02-12 | E-MTAB-5576 | biostudies-arrayexpress

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