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Conditional modeling of MLL-AF9 induced leukemia revealed a stem cell derived aggressive disease [RNA-Seq]

ABSTRACT: To address the impact of cellular origin on AML, we generated an inducible transgenic mouse model for MLL-AF9 driven leukemia. MLL-AF9 expression in long-term hematopoietic stem cells (LT-HSCs) in vitro resulted in unprecedented clonogenic growth and expression of genes involved in migration and invasion. In vivo, some LT-HSC-derived AMLs were particularly aggressive with extensive tissue infiltration, chemo-resistance and expression of genes related to epithelial-mesenchymal transition (EMT) in solid cancers. Knockdown of the EMT regulators Zeb1 and Tcf4 significantly reduced leukemic blast invasion. By classifying mouse and human leukemia according to Evi1/EVI1and Erg/ERG expression, reflecting aggressiveness and cell-of-origin and performing comparative transcriptomics we identified numerous EMT-related genes that were significantly associated with poor overall survival of AML patients. RNA from FACS sorted bone marrow subpopulations was isolated, RNA-sequencing libraries were prepared and sequenced on an Illumina HiSeq 2000. Reads mapping to RefSeq transcripts were counted.

ORGANISM(S): Mus musculus

SUBMITTER: Antoine Peters

PROVIDER: E-GEOD-65383 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Conditional modeling of MLL-AF9 induced leukemia revealed a stem cell derived aggressive disease

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

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2013-06-20 | E-GEOD-45579 | biostudies-arrayexpress

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A comparative epigenomics approach reveals REST as a mediator of Polycomb reprogramming during neuronal differentiation

Project description:Transcription factors (TFs) in concert with chromatin pathways stably reset transcriptional programs during differentiation. Yet we know little how local sites of chromatin reprogramming are specified and how the estimated 3000 TF encoded in mammalian genomes contribute to chromatin dynamics. To identify candidate TFs we developed an integrated computational approach (Epi-MARA) that models chromatin dynamics in terms of predicted transcription factor binding sites and show that it correctly predicts key TFs involved in epigenome reorganization. When applied to a time course of genome-wide H3 lysine 27 trimethylation (H3K27me3), a chromatin mark set by the Polycomb system, during neuronal differentiation of murine stem cells Epi-MARA predicted that the repressive transcription factor REST contributes to a gain of H3K27me3 at a subset of promoters during the transition from the stem to the progenitor state. To test this prediction we identified, genome-wide, the actual binding sites of REST and H3K27me3 during the differentiation in cells that are either wildtype or in which REST had been deleted. REST indeed localizes to a subset of sites that gain H3K27me3 in progenitors. Importantly, absence of REST in trans leads to a loss of H3K27me3 predominantly in the neuronal progenitor state and specifically at those regions where REST was bound. This function further requires REST binding sites in cis as their mutation leads to substantial loss of H3K27me3. Taken together we provide a novel approach to identify epigenome and TF crosstalk during cellular reprogramming and prove experimentally the prediction that REST acts as an important recruiter of Polycomb repression during early steps of neurogenesis. Dataset comprises of 15 ChIP-seq samples using chromatin from embryonic stem (ES) and neuronal progentor (NP) of wildtype and RESTko cells, which was immunoprecipitated, using antibodies against REST, H3K27me3, or Suz12

2012-09-04 | E-GEOD-27148 | biostudies-arrayexpress

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2011-12-22 | E-GEOD-30280 | biostudies-arrayexpress

Total RNA sequencing for Mus musculus bone marrow lymphoid committed cell populations

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Transcription profiling of Lgr6+ keratinocyte populations in the epidermis and hair follicle

Project description:RNA sequencing was performed on sorted populations of Lgr6-positive and Lgr6-negative keratinocytes from the interfollicular epidermis and the hair follicle/sebaceous gland, in order to determine the compartment-specific expression signatures of Lgr6+ progenitor cells.

2015-10-22 | E-MTAB-3533 | biostudies-arrayexpress

A chromatin-modifying function of JNK during stem cell differentiation

Project description:Signaling mediates cellular responses to extracellular stimuli. The c-Jun NH2-terminal kinase (JNK) pathway exemplifies one sub-group of Mitogen-activated protein (MAP) kinases, which besides established functions in stress response, also contributes to developmental processes by an unknown mechanism 1-4. Here we show by genome-wide location analysis that JNK binds directly to a large set of active promoters during differentiation of stem cells to neurons. Bound promoters are not enriched for the canonical AP?1 target sites yet for binding motifs for the transcription factor NF?Y. NF-Y indeed occupies these predicted sites genome-wide in vivo and overexpression of a dominant-negative form of NF?YA reduces JNK presence on chromatin. Histone H3 is a substrate for JNK kinase activity in vitro and JNK bound promoters are preferentially enriched for Histone H3 phosphorylated at Serine 10. Inhibition of JNK signaling in postmitotic neurons reduces this chromatin phosphorylation as well as expression of target genes. Together this establishes MAP kinase binding and function on chromatin at a novel class of target genes during stem cell differentiation. Our Dataset comprises 5 ChIP-seq samples using chromatin from ES, NP and TN cells which was immunoprecipitated, using antibodies against H3K27me3, H3K4me2, RNA Pol II, JNK1/3 and NF-YA. From the same cells we generated biological replicates of RNA-seq data.

2011-12-18 | E-GEOD-25532 | biostudies-arrayexpress

Genomic prevalence of heterochromatic H3K9me2 and transcription do not discriminate pluripotent from terminally differentiated cells (ChIP-seq)

Project description:Cellular differentiation entails reprogramming of the transcriptome from a pluripotent to a unipotent fate. This process was suggested to coincide with a global increase of repressive heterochromatin, which results in a reduction of transcriptional plasticity and potential. Here we report the dynamics of the transcriptome and an abundant heterochromatic histone modification, dimethylation of histone H3 at lysine 9 (H3K9me2), during neuronal differentiation of embryonic stem cells. In contrast to the prevailing model, we find H3K9me2 to occupy over 50% of chromosomal regions already in stem cells. Marked are most genomic regions that are devoid of transcription and a subgroup of histone modifications. Importantly, no global increase occurs during differentiation, but discrete local changes of H3K9me2 particularly at genic regions can be detected. Mirroring the cell fate change many genes show altered expression upon differentiation. Quantitative sequencing of transcripts reveals however that the total number of active genes is equal between stem cells and several tested differentiated cell types. Together, these findings reveal high prevalence of a heterochromatic mark in stem cells and challenge the model of low abundance of epigenetic repression and resulting global transcription in stem cells. Instead cellular differentiation entails local rather than global changes in epigenetic repression and transcriptional activity. Our dataset comprises of 2 ChIP-seq samples using chromatin from embryonic stem (ES) cells and derived terminal neurons (TN) which was immunoprecipitated, using antibodies against H3K27me3 and H3K4me2. For the same cells we generated H3K9me2 ChIP-chip samples in biological replicates. For ES cells, neurons and mouse embryonic fibroblasts (MEFs) we generated biological replicates of RNA-seq data.

2011-06-21 | E-GEOD-27827 | biostudies-arrayexpress

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