BRD4 ChIP-seq in JQ1 treatment and control in MDA-MB-231 cells.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE219192 | GEO | 2023/12/31
REPOSITORIES: GEO
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Project description:METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC, also known as m6A writer) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on mouse embryonic stem cell (mESC) self-renewal. While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-indenepent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification and PRC2 complex. Mechanically, METTL14, but not METTL3, recognizes H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression . The regulation of H3K27me3 by METTL14 is essential to the transition of mESCs from self-renewal to differentiation. This work reveals a regulation mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance and differentiation of mESCs.
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Project description:METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC, also known as m6A writer) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on mouse embryonic stem cell (mESC) self-renewal. While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-indenepent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification and PRC2 complex. Mechanically, METTL14, but not METTL3, recognizes H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression . The regulation of H3K27me3 by METTL14 is essential to the transition of mESCs from self-renewal to differentiation. This work reveals a regulation mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance and differentiation of mESCs.
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Project description:METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC, also known as m6A writer) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on mouse embryonic stem cell (mESC) self-renewal. While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-indenepent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification and PRC2 complex. Mechanically, METTL14, but not METTL3, recognizes H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression . The regulation of H3K27me3 by METTL14 is essential to the transition of mESCs from self-renewal to differentiation. This work reveals a regulation mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance and differentiation of mESCs.
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Project description:METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC, also known as m6A writer) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on mouse embryonic stem cell (mESC) self-renewal. While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-indenepent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification and PRC2 complex. Mechanically, METTL14, but not METTL3, recognizes H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression . The regulation of H3K27me3 by METTL14 is essential to the transition of mESCs from self-renewal to differentiation. This work reveals a regulation mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance and differentiation of mESCs.
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Project description:N6-methyladenosine (m6A) methylation of mRNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the mechanism of MTC assembly remains elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3), that is highly expressed in breast cancer. Furthermore, we find that both METTL3a and full-length METTL3 are required for MTC assembly, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is required for METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC assembly. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A methylation, and METTL3a mediates mTOR activation via m6A-mediated suppression of TMEM127 expression. Consequently, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component for MTC assembly, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.
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Project description:Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex (MTC) that catalyzes mRNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent function of the MTC, m6A independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 drives senescence-associated secretory phenotype (SASP) in a m6A-independent manner. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL14 is redistributed to the enhancers, while METTL3 is localized to the pre-existing NF-B sites within the promoters of the SASP genes during senescence. METTL3 interacts with NF-B and they are mutually dependent on their associations with the promoters of SASP genes. METTL14 but not METTL3 is necessary for function of SASP gene enhancers. METTL3 and METTL14 are required for both the tumor-promoting and immune surveillance functions of senescent cells mediated by SASP in vivo in mouse models. In summary, our results report a m6A independent function of the METTL3 and METTL14 complex in promoting SASP through regulating transcription by genome-wide redistribution of METTL14 to enhancers and METTL3 to promoters of SASP genes during senescence.
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Project description:Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex (MTC) that catalyzes mRNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent function of the MTC, m6A independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 drives senescence-associated secretory phenotype (SASP) in a m6A-independent manner. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL14 is redistributed to the enhancers, while METTL3 is localized to the pre-existing NF-B sites within the promoters of the SASP genes during senescence. METTL3 interacts with NF-B and they are mutually dependent on their associations with the promoters of SASP genes. METTL14 but not METTL3 is necessary for function of SASP gene enhancers. METTL3 and METTL14 are required for both the tumor-promoting and immune surveillance functions of senescent cells mediated by SASP in vivo in mouse models. In summary, our results report a m6A independent function of the METTL3 and METTL14 complex in promoting SASP through regulating transcription by genome-wide redistribution of METTL14 to enhancers and METTL3 to promoters of SASP genes during senescence.
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Project description:Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex (MTC) that catalyzes mRNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent function of the MTC, m6A independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 drives senescence-associated secretory phenotype (SASP) in a m6A-independent manner. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL14 is redistributed to the enhancers, while METTL3 is localized to the pre-existing NF-B sites within the promoters of the SASP genes during senescence. METTL3 interacts with NF-B and they are mutually dependent on their associations with the promoters of SASP genes. METTL14 but not METTL3 is necessary for function of SASP gene enhancers. METTL3 and METTL14 are required for both the tumor-promoting and immune surveillance functions of senescent cells mediated by SASP in vivo in mouse models. In summary, our results report a m6A independent function of the METTL3 and METTL14 complex in promoting SASP through regulating transcription by genome-wide redistribution of METTL14 to enhancers and METTL3 to promoters of SASP genes during senescence.
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