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| Status |
Public on Aug 01, 2017 |
| Title |
Mll3 suppresses tumorigenesis by activating the Ink4a/Arf locus [RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Analysis of RNA isolated from liver tumor-derived Myc;sgp53/Cas9 and Myc;sgMll3/Cas9 cell lines.
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| Contributor(s) |
Tschaharganeh D, Huang CH, Morris 4th JP, Lowe S |
| Citation(s) |
37261974 |
| |
| Submission date |
Aug 01, 2016 |
| Last update date |
Jun 08, 2023 |
| Contact name |
Jeffrey Zhao |
| Organization name |
Memorial Sloan Kettering Cancer Center
|
| Department |
Genomics Core
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| Street address |
1275 York Avenue
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE85055 |
Mll3 suppresses tumorigenesis by activating the Ink4a/Arf locus |
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| Relations |
| BioProject |
PRJNA336036 |
| SRA |
SRP080761 |
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