Similar Datasets
Project description:N6-methyladenosine (m6A)methylationcan be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. How the MTC is recruited to distinct genomic loci to accomplish selective transcriptional regulation remains elusive. Here we identify RBFOX2, a well-established RNA-binding protein (RBP), as a chromatin factor that recognizes m6A on caRNAs and recruits RBM15, an MTC component, to install methylation on promoter-associated RNAs (paRNAs). RBM15 also physically interacts with YTHDC1 to facilitate the recruitment of Polycomb repressive complex 2 (PRC2) to RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this m6A/RBM15/YTHDC1/PRC2 axis is essential to myeloid leukemia. Downregulation of RBFOX2 notably inhibits AML cell survival/proliferation and promotes myeloid differentiation of AML cells. RBFOX2 is also required for self-renewal of leukemia stem/initiation cells (LSCs/ LICs) and AML maintenance. Together, our study presents a clear pathway of m6A MTC recruitment and m6A deposition on caRNAs to achieve locus-specific chromatin regulation with potential therapeutic implications.
2023-06-16 | GSE229013 | GEO
Project description:N6-methyladenosine (m6A)methylationcan be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. How the MTC is recruited to distinct genomic loci to accomplish selective transcriptional regulation remains elusive. Here we identify RBFOX2, a well-established RNA-binding protein (RBP), as a chromatin factor that recognizes m6A on caRNAs and recruits RBM15, an MTC component, to install methylation on promoter-associated RNAs (paRNAs). RBM15 also physically interacts with YTHDC1 to facilitate the recruitment of Polycomb repressive complex 2 (PRC2) to RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this m6A/RBM15/YTHDC1/PRC2 axis is essential to myeloid leukemia. Downregulation of RBFOX2 notably inhibits AML cell survival/proliferation and promotes myeloid differentiation of AML cells. RBFOX2 is also required for self-renewal of leukemia stem/initiation cells (LSCs/ LICs) and AML maintenance. Together, our study presents a clear pathway of m6A MTC recruitment and m6A deposition on caRNAs to achieve locus-specific chromatin regulation with potential therapeutic implications.
2023-06-16 | GSE229012 | GEO
Project description:N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. How the MTC is recruited to distinct genomic loci to accomplish selective transcriptional regulation remains elusive. Here we identify RBFOX2, a well-established RNA-binding protein (RBP), as a chromatin factor that recognizes m6A on caRNAs and recruits RBM15, an MTC component, to install methylation on promoter-associated RNAs (paRNAs). RBM15 also physically interacts with YTHDC1 to facilitate the recruitment of Polycomb repressive complex 2 (PRC2) to RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this m6A/RBM15/YTHDC1/PRC2 axis is essential to myeloid leukemia. Downregulation of RBFOX2 notably inhibits AML cell survival/proliferation and promotes myeloid differentiation of AML cells. RBFOX2 is also required for self-renewal of leukemia stem/initiation cells (LSCs/ LICs) and AML maintenance. Together, our study presents a clear pathway of m6A MTC recruitment and m6A deposition on caRNAs to achieve locus-specific chromatin regulation with potential therapeutic implications.
2023-06-16 | GSE205710 | GEO
Project description:N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. How the MTC is recruited to distinct genomic loci to accomplish selective transcriptional regulation remains elusive. Here we identify RBFOX2, a well-established RNA-binding protein (RBP), as a chromatin factor that recognizes m6A on caRNAs and recruits RBM15, an MTC component, to install methylation on promoter-associated RNAs (paRNAs). RBM15 also physically interacts with YTHDC1 to facilitate the recruitment of Polycomb repressive complex 2 (PRC2) to RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this m6A/RBM15/YTHDC1/PRC2 axis is essential to myeloid leukemia. Downregulation of RBFOX2 notably inhibits AML cell survival/proliferation and promotes myeloid differentiation of AML cells. RBFOX2 is also required for self-renewal of leukemia stem/initiation cells (LSCs/ LICs) and AML maintenance. Together, our study presents a clear pathway of m6A MTC recruitment and m6A deposition on caRNAs to achieve locus-specific chromatin regulation with potential therapeutic implications.
2023-06-16 | GSE205709 | GEO
Project description:N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. How the MTC is recruited to distinct genomic loci to accomplish selective transcriptional regulation remains elusive. Here we identify RBFOX2, a well-established RNA-binding protein (RBP), as a chromatin factor that recognizes m6A on caRNAs and recruits RBM15, an MTC component, to install methylation on promoter-associated RNAs (paRNAs). RBM15 also physically interacts with YTHDC1 to facilitate the recruitment of Polycomb repressive complex 2 (PRC2) to RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this m6A/RBM15/YTHDC1/PRC2 axis is essential to myeloid leukemia. Downregulation of RBFOX2 notably inhibits AML cell survival/proliferation and promotes myeloid differentiation of AML cells. RBFOX2 is also required for self-renewal of leukemia stem/initiation cells (LSCs/ LICs) and AML maintenance. Together, our study presents a clear pathway of m6A MTC recruitment and m6A deposition on caRNAs to achieve locus-specific chromatin regulation with potential therapeutic implications.
2023-06-16 | GSE205708 | GEO
Project description:N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. How the MTC is recruited to distinct genomic loci to accomplish selective transcriptional regulation remains elusive. Here we identify RBFOX2, a well-established RNA-binding protein (RBP), as a chromatin factor that recognizes m6A on caRNAs and recruits RBM15, an MTC component, to install methylation on promoter-associated RNAs (paRNAs). RBM15 also physically interacts with YTHDC1 to facilitate the recruitment of Polycomb repressive complex 2 (PRC2) to RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this m6A/RBM15/YTHDC1/PRC2 axis is essential to myeloid leukemia. Downregulation of RBFOX2 notably inhibits AML cell survival/proliferation and promotes myeloid differentiation of AML cells. RBFOX2 is also required for self-renewal of leukemia stem/initiation cells (LSCs/ LICs) and AML maintenance. Together, our study presents a clear pathway of m6A MTC recruitment and m6A deposition on caRNAs to achieve locus-specific chromatin regulation with potential therapeutic implications.
2023-06-16 | GSE205706 | GEO
Project description:We are currently assisting in the explosion of epitranscriptomics, which studies the functional role of chemical modifications into RNA molecules. Among more than 100 RNA modifications, the N6-methyladenosine (m?A), in particular, has attracted the interest of researchers all around the world. m?A is the most abundant internal chemical modification in mRNA, and it can control any aspect of mRNA post-transcriptional regulation. m?A is installed by "writers", removed by "erasers", and recognized by "readers"; thus, it can be compared to the reversible and dynamic epigenetic modifications in histones and DNA. Given its fundamental role in determining the way mRNAs are expressed, it comes as no surprise that alterations to m?A modifications have a deep impact in cell differentiation, normal development and human diseases. Here, we review the proteins involved in m?A modification in mammals, m?A role in gene expression and its contribution to cancer development. In particular, we will focus on acute myeloid leukaemia (AML), which provides an initial indication of how alteration in m?A modification can disrupt normal cellular differentiation and lead to cancer.
| S-EPMC6121471 | biostudies-literature
Project description:N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.
| S-EPMC5677536 | biostudies-literature
Project description:N6-methyladenosine (m6A) serves a critical role in regulating gene expression and has been associated with various diseases; however, its role in the differentiation of endothelial progenitor cells (EPCs) remains unclear. The present study used liquid chromatography with tandem mass spectrometry and immunofluorescence assays to quantify the levels of m6A in human peripheral blood-derived EPCs (HPB-EPCs) before and after differentiation into mature cells. The present study performed Cell Counting Kit 8, Transwell, and tube formation assays to determine the effects of overexpression and knockdown of Wilms' tumor 1-associated protein (WTAP) on HPB-EPCs. The results revealed that the level of m6A modification was significantly increased during HPB-EPCs differentiation, and WTAP exhibited the most significant alteration among the enzymes involved in m6A regulation. When WTAP was overexpressed in HPB-EPCs, cell proliferation, invasion, and the formation of tubes were improved, whereas WTAP knockdown yielded the opposite effects. In conclusion, the present study highlighted the involvement of m6A in regulating EPC differentiation, with WTAP acting as a promoter of EPC differentiation.
| S-EPMC10433437 | biostudies-literature
Project description:One of the defining features of acute myeloid leukemia (AML) is an arrest of myeloid differentiation whose molecular determinants are still poorly defined. Pharmacological removal of the differentiation block contributes to the cure of acute promyelocytic leukemia (APL) in the absence of cytotoxic chemotherapy, but this approach has not yet been translated to non-APL AMLs. Here, by investigating the function of hypoxia-inducible transcription factors HIF1a and HIF2a we found that both genes exert oncogenic functions in AML and that HIF2a is a novel regulator of the AML differentiation block. Mechanistically, we found that HIF2a promotes the expression of transcriptional repressors that have been implicated in suppressing AML myeloid differentiation programs. Importantly, we positioned HIF2a under direct transcriptional control by the pro-differentiation agent all-trans retinoic acid (ATRA) and demonstrated that HIF2a blockade cooperates with ATRA to trigger AML cell differentiation. In conclusion, we propose that HIF2a inhibition may open new therapeutic avenues for AML treatment by licensing blasts maturation and leukemia debulking.
| S-SCDT-10_15252-EMMM_202317810 | biostudies-other