Dataset Information

N⁶-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.

ABSTRACT: N⁶-Methyladenosine (m⁶A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m⁶A dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential m⁶A reader in myeloid leukemia from a genome-wide CRISPR screen and that m⁶A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m⁶A condensates (nYACs). The number of nYACs increases in acute myeloid leukemia (AML) cells compared with normal hematopoietic stem and progenitor cells. AML cells require the nYACs to maintain cell survival and the undifferentiated state that is critical for leukemia maintenance. Furthermore, nYACs enable YTHDC1 to protect m⁶A-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, m⁶A is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC8282764 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.

Cheng Yuanming Y Xie Wei W Pickering Brian F BF Chu Karen L KL Savino Angela M AM Yang Xuejing X Luo Hanzhi H Nguyen Diu Tt DT Mo Shanlan S Barin Ersilia E Velleca Anthony A Rohwetter Thomas M TM Patel Dinshaw J DJ Jaffrey Samie R SR Kharas Michael G MG

Cancer cell 20210527 7

N6-Methyladenosine (m6A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m6A dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential m6A reader in myeloid leukemia from a genome-wide CRISPR screen and that m6A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m6A condensate ...[more]

PMID: 34048709

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Project description:BackgroundN6-methyladenosine (m6 A) modification is the most common modification that occurs in eukaryotes. Although substantial effort has been made in the prevention and treatment of gastric cancer (GC) in recent years, the prognosis of GC patients remains unsatisfactory. The regulatory mechanism between m6 A modification and GC development needs to be elucidated. In this study, we examined m6 A modification and the downstream mechanism in GC.MethodsDot blotting assays, The Cancer Genome Atlas analysis, and quantitative real-time PCR (qRT-PCR) were used to measure the m6 A levels in GC tissues. Methylated RNA-immunoprecipitation sequencing and RNA sequencing were performed to identify the targets of m6 A modification. Western blotting, Transwell, wound healing, and angiogenesis assays were conducted to examine the role of centromere protein F (CENPF) in GC in vitro. Xenograft, immunohistochemistry, and in vivo metastasis experiments were conducted to examine the role of CENPF in GC in vivo. Methylated RNA-immunoprecipitation-qPCR, RNA immunoprecipitation-qPCR and RNA pulldown assays were used to verify the m6 A modification sites of CENPF. Gain/loss-of-function and rescue experiments were conducted to determine the relationship between CENPF and the mitogen-activated protein kinase (MAPK) signaling pathway in GC cells. Coimmunoprecipitation, mass spectrometry, qRT-PCR, and immunofluorescence assays were performed to explore the proteins that interact with CENPF and elucidate the regulatory mechanisms between them.ResultsCENPF was upregulated in GC and facilitated the metastasis of GC both in vitro and in vivo. Mechanistically, increased m6 A modification of CENPF was mediated by methyltransferase 3, and this modified molecule could be recognized by heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), thereby promoting its mRNA stability. In addition, the metastatic phenotype of CENPF was dependent on the MAPK signaling pathway. Furthermore, CENPF could bind to FAK and promote its localization in the cytoplasm. Moreover, we discovered that high expression of CENPF was related to lymphatic invasion and overall survival in GC patients.ConclusionsOur findings revealed that increased m6 A modification of CENPF facilitates the metastasis and angiogenesis of GC through the CENPF/FAK/MAPK and epithelial-mesenchymal transition axis. CENPF expression was correlated with the clinical features of GC patients; therefore, CENPF may serve as a prognostic marker of GC.

Project description:Plants respond to low temperatures by altering the mRNA abundance of thousands of genes contributing to numerous physiological and metabolic processes that allow them to adapt. At the post-transcriptional level, these cold stress-responsive transcripts undergo alternative splicing, microRNA-mediated regulation and alternative polyadenylation, amongst others. Recently, m6 A, m5 C and other mRNA modifications that can affect the regulation and stability of RNA were discovered, thus revealing another layer of post-transcriptional regulation that plays an important role in modulating gene expression. The importance of m6 A in plant growth and development has been appreciated, although its significance under stress conditions is still underexplored. To assess the role of m6 A modifications during cold stress responses, methylated RNA immunoprecipitation sequencing was performed in Arabidopsis seedlings esposed to low temperature stress (4°C) for 24 h. This transcriptome-wide m6 A analysis revealed large-scale shifts in this modification in response to low temperature stress. Because m6 A is known to affect transcript stability/degradation and translation, we investigated these possibilities. Interestingly, we found that cold-enriched m6 A-containing transcripts demonstrated the largest increases in transcript abundance coupled with increased ribosome occupancy under cold stress. The significance of the m6 A epitranscriptome on plant cold tolerance was further assessed using the mta mutant in which the major m6 A methyltransferase gene was mutated. Compared to the wild-type, along with the differences in CBFs and COR gene expression levels, the mta mutant exhibited hypersensitivity to cold treatment as determined by primary root growth, biomass, and reactive oxygen species accumulation. Furthermore, and most importantly, both non-acclimated and cold-acclimated mta mutant demonstrated hypersensitivity to freezing tolerance. Taken together, these findings suggest a critical role for the epitranscriptome in cold tolerance of Arabidopsis.

Dataset Information

N⁶-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.

Publications

N<sup>6</sup>-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.

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