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Mutation of cancer driver MLL2 results in transcription stress and genome instability

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Theo Kantidakis

PROVIDER: E-GEOD-73130 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Mutation of cancer driver MLL2 results in transcription stress and genome instability.

Kantidakis Theodoros T Kantidakis Theodoros T Saponaro Marco M Mitter Richard R Horswell Stuart S Kranz Andrea A Boeing Stefan S Aygün Ozan O Kelly Gavin P GP Matthews Nik N Stewart Aengus A Stewart A Francis AF Svejstrup Jesper Q JQ

Genes & development 20160201 4

Genome instability is a recurring feature of tumorigenesis. Mutation in MLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence that MLL2 mutation results in genome instability. Mouse cells in which MLL2 gene deletion can be induced display elevated levels of sister chromatid exchange, gross chromosomal aberrations, 53BP1 foci, and micronuclei. Human MLL2 knockout cells are characterized by genome instabi ...[more]

PMID: 26883360

Similar Datasets

Mutation of cancer driver MLL2 results in transcription stress and genome instability.

Project description:Genome instability is a recurring feature of tumorigenesis. Mutation in MLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence that MLL2 mutation results in genome instability. Mouse cells in which MLL2 gene deletion can be induced display elevated levels of sister chromatid exchange, gross chromosomal aberrations, 53BP1 foci, and micronuclei. Human MLL2 knockout cells are characterized by genome instability as well. Interestingly, MLL2 interacts with RNA polymerase II (RNAPII) and RECQL5, and, although MLL2 mutated cells have normal overall H3K4me levels in genes, nucleosomes in the immediate vicinity of RNAPII are hypomethylated. Importantly, MLL2 mutated cells display signs of substantial transcription stress, and the most affected genes overlap with early replicating fragile sites, show elevated levels of γH2AX, and suffer frequent mutation. The requirement for MLL2 in the maintenance of genome stability in genes helps explain its widespread role in cancer and points to transcription stress as a strong driver in tumorigenesis.

| S-EPMC4762426 | biostudies-literature

RECQL5 Controls Transcript Elongation and Suppresses Transcription-Associated Genome Instability

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-06-09 | E-GEOD-49134 | biostudies-arrayexpress

Mapping of nascent RNA in MLL2 F/F and FC/FC MEF cells

Project description:Global Run-On has been performed in MLL2 F/F and FC/FC MEF cells. The aim of the experiment is to test how the lack of MLL2 affects nascent RNA transcription. Four samples were analyzed - 2 independent replicates. The experiments were performed using immortalized mouse embryonic fibroblasts (MEF) in which both MLL2 alleles were targeted by the loxp system (F/F cells). Tamoxifen treatment of the F/F cells for 24 hours results in the excision of both MLL2 alleles (FC/FC cells).

2016-04-13 | E-GEOD-73126 | biostudies-arrayexpress

Mutation of cancer driver MLL2 results in transcription stress and genome instability

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-04-13 | GSE73130 | GEO

Genome wide profiling of the RNAPII, Î³H2AX, H3K4Me1, H3K4M2 and H3K4Me3 in MLL2 F/F and FC/FC MEF cells

Project description:We investigated the RNAPII and Î³H2AX occupancy genome wide by ChIP-Seq in MLL2 F/F and FC/FC80 MEF cells. We found that a week after MLL2 excision (FC/FC cells), a group of genes present higher levels of Î³H2AX and RNAPII near the TSS, as compared to the control (F/F cells). H3K4Me1, H3K4M2 and H3K4Me3 levels near the TSS were also studied. There is a total of 52 samples. 3 independent replicates for each experiment were performed. H3, H2AX and IgG ChIPs were used for normalisation or as controls.The experiments were performed using immortalised mouse embryonic fibroblasts (MEF) in which both MLL2 alleles were targeted by the loxp system (F/F cells). Tamoxifen treatment of the F/F cells for 24 hours results in the excision of both MLL2 alleles (FC/FC cells).

2016-04-13 | E-GEOD-73124 | biostudies-arrayexpress

Sequence database choice significantly affects taxonomic and functional metaproteomic results in gut microbiota studies

Project description:Elucidating the role of gut microbiota in physiological and pathological processes has recently emerged as a key research aim in life sciences. In this respect, metaproteomics (the study of the whole protein complement of a microbial community) can provide a unique contribution by revealing which functions are actually being expressed by specific microbial taxa. However, its wide application to gut microbiota research has been hindered by challenges in data analysis, especially related to the choice of the proper sequence databases for protein identification. Here we present a systematic investigation of variables concerning database construction and annotation, and evaluate their impact on human and mouse gut metaproteomic results. We found that both publicly available and experimental metagenomic databases lead to the identification of unique peptide assortments, suggesting parallel database searches as a mean to gain more complete information. Taxonomic and functional results were revealed to be strongly database-dependent, especially when dealing with mouse samples. As a striking example, in mouse the Firmicutes/Bacteroidetes ratio varied up to 10-fold depending on the database used. Finally, we provide recommendations regarding metagenomic sequence processing aimed at maximizing gut metaproteome characterization, and contribute to identify an optimized pipeline for metaproteomic data analysis.

2016-10-10 | PXD004039 | Pride

Mapping of nascent RNA upon release of DRB in WT and KD of RECQL5

Project description:Global Run-On has been performed on WT or KD for RECQL5 cells after release from DRB. When RECQL5 is knocked-down the transcriptional wave front is more advanced, suggesting that transcription is faster. Constitutive knock-down cell lines expressing or not endogenous levels of shRNA resistant RECQL5 under a Doxycycline inducible promoter were treated with high doses of DRB to block transcription. Upon release into fresh medium we were able to follow how much and how fast the RNA Pol II progresses through genes by mapping nascent RNA by Run-On. The experiment was performed in two cell line clones.

2014-06-09 | E-GEOD-49133 | biostudies-arrayexpress

Identification of MLL2 regulated genes in germinal center B cells

Project description:Somatic mutations of the MLL2 methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), these mutations are highly recurrent and occur early during tumorigenesis, suggesting a central role in transformation. Here we show that FL/DLBCL-associated MLL2 mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in germinal center (GC) B cells and DLBCL, consistent with the enrichment of MLL2 binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Mll2 early during B cell development, but not after initiation of the GC reaction, leads to an increase in GC B cells, whose transcriptional profile is enriched in cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Mll2-deficient B cells exhibit proliferative advantage ex vivo. Loss of Mll2 combined with BCL2 deregulation, mimicking FL/DLBCL pathogenesis, leads to an increased incidence of clonal lymphoproliferations resembling the features of the human tumors. These findings suggest that early MLL2 loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of MLL2-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events. ChIP-seq analysis of MLL2 bound regions and histone methylation (H3K4me3, H3K4me1) in normal human germinal center B cells.

2015-09-10 | E-GEOD-67494 | biostudies-arrayexpress

A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

Project description:Our data throw light upon the effect of WRN deficiency on gene expression and epigenomic modification, which indicates aging-associated changes from both genomic and epigenomic level. It was compared between WRN+/+ and WRN-/- in hESCs and hMSCs that the gene expression landscapes and epigenetic modifications(H3K4me3, H3K27me3, H3K9me3 and 5-methylcytosine).

2015-05-13 | E-GEOD-52285 | biostudies-arrayexpress

OGT, H2B S112GlcNAc, TET2 ChIP-seq results

Project description:TET2 directly interacts with OGT, which is important for the chromatin association of OGT in vivo. Although this specific interaction does not regulate the enzymatic activity of TET2, it facilitates OGT-dependent histone O-GlcNAcylation. Moreover, OGT associates with TET2 at transcription starting sites (TSS). Down-regulation of TET2 reduces the amount of H2B S112 GlcNAc marks in vivo, which are associated with gene transcription regulation. We found that OGT interacts with TET2 tightly. Using ChIP-seq with specific antibodies, we tested the co-localization of TET2 and OGT in genome level.

2012-12-11 | E-GEOD-41720 | biostudies-arrayexpress

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