Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Notch1-driven epigenetic changes in a mouse model of T cell Acute Lymphoblastic Leukemia (T-ALL)

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we used a mouse model of T-ALL through the overexpression of the intarcellular transcriptionally active part of Notch1 (N1-IC). This model faithfully recapitulates the major characteristics of the human disease. Comparison of the leukemic cells from peripheral tumors(thymoma) of this mouse model to normal thymic cells Double Positive (DP) for the markers CD4 and CD8 that express very low levels of Notch1 showed major expression changes (please see GSE34554) in pathways controlling the transition from physiology to disease. Further correlation of the data to ChIP-Seq data from the same cell populations led us to identify a hitherto unknown antagonism of the Notch1 oncogenic pathway and the polycomb complex (PRC2) in leukemia. Importantly exome sequencing in primary samples from human patients with T-ALL revealed that the PRC2 complex is frequently mutated and inactivated, further supporting the tumor suppressor role of the complex in this disease. Gene expression profiles from CD4+/8+ Double Positive (named DP) derived from normal thymus and Notch1-IC over-expressing tumors (named T-ALL) were analyzed for the genomewide enrichments of two major activating epigenetic marks (Histone 3 Lysine 9 acetylation (H3K9ac) and lysine 4 trimethylation (H3K4me3)), one reprressive mark (Histone 3 lysine 27 trimethylation, H3K27me3) and the major oncogene Notch1.

ORGANISM(S): Mus musculus

SUBMITTER: Aristotelis Tsirigos

PROVIDER: E-GEOD-34954 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia.

Ntziachristos Panagiotis P Tsirigos Aristotelis A Van Vlierberghe Pieter P Nedjic Jelena J Trimarchi Thomas T Flaherty Maria Sol MS Ferres-Marco Dolors D da Ros Vanina V Tang Zuojian Z Siegle Jasmin J Asp Patrik P Hadler Michael M Rigo Isaura I De Keersmaecker Kim K Patel Jay J Huynh Tien T Utro Filippo F Poglio Sandrine S Samon Jeremy B JB Paietta Elisabeth E Racevskis Janis J Rowe Jacob M JM Rabadan Raul R Levine Ross L RL Brown Stuart S Pflumio Francoise F Dominguez Maria M Ferrando Adolfo A Aifantis Iannis I

Nature medicine 20120206 2

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-spe ...[more]

PMID: 22237151

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Project description:Specific histone modifications play important roles in chromatin functions such as activation or repression of gene transcription. These participation must occur as a dynamic process, however, most of histone modification state maps reported to date only provide static pictures linking certain modification with active or silenced states. This study focused on the global histone modification variation that occurs in response to transcriptional reprogramming produced by a physiological perturbation in yeast. We have performed genome-wide chromatin immunoprecipitation analysis for eight specific histone modifications before and after of a saline stress. The most striking change is a quick deacetylation of lysines 9 and 14 of H3 and lysine 8 of H4 associated to repression of genes. Genes that are activated increase the acetylation levels at these same sites, but this acetylation process of activated genes seems minor quantitatively to that of the deacetylation of repressed genes. The observed changes in tri-methylation of lysines 4, 36 and 79 of H3 and also di-methylation of lysine 79 of H3 are much more moderate than those of acetylation. Additionally, we have produced new genome-wide maps for six histone modifications at more than five times higher resolution of previous available data and analyzed for the first time in S. cerevisiae genome wide profiles of two more, acetylation of lysine 8 of H4 and di-methylation of lysine 79 of H3. In this research we have shown that dynamic of acetylation state of histones during activation or repression of transcription is a process much quicker than methylation and therefore the changes produced in the acetylation may affect methylation but the reverse path is not possible. The experiments described in this study compare ChIP with a histone modification antibody to a control ChIP with a core histone antibody. Budding yeast samples were analyzed in exponential growing conditions (YPD) or after 10 minutes of 0.4M NaCl stress. For each experiment 1 or 2 biological replicates were performed.

Dataset Information

Notch1-driven epigenetic changes in a mouse model of T cell Acute Lymphoblastic Leukemia (T-ALL)

Publications

Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia.

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