MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA672784 | ENA |
REPOSITORIES: ENA
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Project description:MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity
| PRJNA672702 | ENA
Project description:MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity [ChIP-seq]
| PRJNA672157 | ENA
Project description:MLL3 is a histone H3K4 methyltransferase which is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 knockout by CRISPR/sgRNA did not elevate proliferation rate of cancer cells, but significantly enhanced cell migration. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused down regulation of H3K4me1 and H3K27ac on an enhancer ~ 8 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter, and repression of enhancer with dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.
2021-04-14 | GSE160253 | GEO
Project description:MLL3 is a histone H3K4 methyltransferase which is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 knockout by CRISPR/sgRNA did not elevate proliferation rate of cancer cells, but significantly enhanced cell migration. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused down regulation of H3K4me1 and H3K27ac on an enhancer ~ 8 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter, and repression of enhancer with dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.
2021-04-14 | GSE160164 | GEO
Project description: Not available
| S-EPMC8024252 | biostudies-literature
Project description:Mutations in genes encoding epigenetic regulators are among the most frequent somatic events in human cancers. For example, missense and truncating mutations in the MLL3 (KTM2C) histone H3K4-methyltransferase gene can be found in several tumor types. MLL3 is a member of the mixed lineage leukemia gene family and component of the mammalian COMPASS/like complex that promotes gene expression by establishing chromatin modifications favoring gene activation. While Mll3 loss of function promotes tumorigenesis in mice, the molecular targets and biological processes underlying its anti-neoplastic effects remain unknown. Here we combine powerful genetic, genomic, and animal modeling approaches to demonstrate that Mll3 suppresses hepatocellular carcinoma (HCC) by promoting activation of the Cdkn2a (Ink4a/Arf) locus. Hence, disruption of Mll3 using CRISPR/Cas9-mediated genome editing or by RNA interference using short hairpin RNAs cooperates with the Myc oncogene to drive tumorigenesis, producing tumors with reduced H3K4 methylation at multiple gene regulatory elements and low levels of p16Ink4a and p19Arf expression. These results place MLL3 in an established tumor suppressor network and reveal how disruption of a conserved mechanism of epigenetic regulation can alter CDKN2A action and cancer development.
2017-08-01 | GSE85053 | GEO
Project description:Mutations in genes encoding epigenetic regulators are among the most frequent somatic events in human cancers. For example, missense and truncating mutations in the MLL3 (KTM2C) histone H3K4-methyltransferase gene can be found in several tumor types. MLL3 is a member of the mixed lineage leukemia gene family and component of the mammalian COMPASS/like complex that promotes gene expression by establishing chromatin modifications favoring gene activation. While Mll3 loss of function promotes tumorigenesis in mice, the molecular targets and biological processes underlying its anti-neoplastic effects remain unknown. Here we combine powerful genetic, genomic, and animal modeling approaches to demonstrate that Mll3 suppresses hepatocellular carcinoma (HCC) by promoting activation of the Cdkn2a (Ink4a/Arf) locus. Hence, disruption of Mll3 using CRISPR/Cas9-mediated genome editing or by RNA interference using short hairpin RNAs cooperates with the Myc oncogene to drive tumorigenesis, producing tumors with reduced H3K4 methylation at multiple gene regulatory elements and low levels of p16Ink4a and p19Arf expression. These results place MLL3 in an established tumor suppressor network and reveal how disruption of a conserved mechanism of epigenetic regulation can alter CDKN2A action and cancer development.
2017-08-01 | GSE85049 | GEO
Project description:Mll3 suppresses tumorigenesis by activating the Ink4a/Arf locus
| PRJNA336025 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-04-14 | GSE160254 | GEO
Project description:Enhancers play a key role in regulating cell type-specific gene expression and are marked by histone modifications such as methylation and acetylation. Mono-methylation of lysine 4 on histone H3 (H3K4me1) initially primes enhancers, preceding enhancer activation via acetylation of lysine 27 on histone H3 (H3K27ac). MLL4 is a major enhancer H3K4 mono-methyltransferase with partial functional redundancy with MLL3. However, how H3K4me1 affects enhancer regulation in cell differentiation has remained unclear. By screening several lysine-to-methionine mutants of H3.3, we first found that depletion of H3K4 methylation by H3.3K4M mutation severely impairs adipogenesis in culture. Using tissue-specific expression of H3.3K4M in mice, we further demonstrate that H3.3K4M inhibits adipose tissue and muscle development in vivo. Mechanistically, H3.3K4M destabilizes MLL3/4 proteins but not other members of the mammalian Set1-like H3K4 methyltransferase family and prevents MLL3/4-mediated enhancer activation in adipogenesis. Using tissue-specific deletion of the enzymatic SET domain of MLL3/4 in mice, we also show that deletion of the SET domain prevents adipose tissue and muscle development in vivo and inhibits adipogenesis by destabilizing MLL3/4 in vitro. Notably, H3.3K4M expression mimics MLL3/4 SET domain deletion in preventing adipogenesis. Interestingly, H3.3K4M does not affect adipose tissue maintenance and function, suggesting that MLL3/4-mediated H3K4 methylation is dispensable for the maintenance and function of differentiated adipocytes. Together, our findings suggest that H3.3K4M targets MLL3/4 to prevent enhancer activation in adipogenesis.
2018-10-25 | GSE110972 | GEO