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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Epigenomic Alterations Define Lethal CIMP positive Ependymomas of Infancy

ABSTRACT: Ependymomas are common childhood brain tumors that occur throughout the nervous system, but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic SNVs. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP-positive (CIMP+) hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland. 10 primary posterior fossa ependymomas have been analyzed

ORGANISM(S): Homo sapiens

SUBMITTER: Stephen Christopher

PROVIDER: E-GEOD-55920 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Epigenomic Alterations Define Lethal CIMP positive Ependymomas of Infancy

Project description:Ependymomas are common childhood brain tumors that occur throughout the nervous system, but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic SNVs. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP-positive (CIMP+) hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland.

2014-03-15 | GSE55920 | GEO

Genome-wide mapping of Mash1 from mouse spinal cord

Project description:We performed ChIP-seq on a complex developing tissue (the spinal cord) at mouse embryonic day 12.5. Genome-wide binding sites of Mash1 were generated. ChIP-seq of Mash1/Ascl1 in a heterogeneous tissue.

2013-05-03 | E-GEOD-43159 | biostudies-arrayexpress

The Chromatin-Looping Factor ZNF143 Engages at Looping Promoters to Favor the Estrogen Response in Breast Cancer (ChIP-seq)

Project description:Estrogen signaling in breast cancer cells relies on long-range chromatin interactions connecting distal regulatory elements bound by the estrogen receptor 1 (ESR1) to target gene promoters. This ensures stimulus and subtype-specific transcriptional responses. Expanding on the function of CTCF and the cohesin complex in breast cancer, we demonstrate that the chromatin-looping factor ZNF143 binds the promoter of most early-response estrogen target genes connected to distal regulatory elements in ESR1-positive breast cancer cells. Its chromatin occupancy is unaffected by estrogen stimulation, supporting a stable three-dimensional genomic architecture within the early response to estrogen. Its loss abrogates the estrogen-induced transcriptional response and growth of breast cancer cells. When taking into account CTCF, ZNF143 and cohesin complex subunits, we show that chromatin-looping factors are genetically altered in over 20% of ESR1-positive primary breast tumors. Furthermore, the overexpression of ZNF143, CTCF and RAD21, a cohesin complex subunit, in ESR1-positive breast tumors associates with a worse clinical outcome. Overall, our results suggest that ZNF143 is a new critical effector of the estrogen response and highlights the contribution of the chromatin looping machinery to ESR1-positive breast cancer development. Examination of genome-wide ZNF143 binding in MCF-7 cells

2016-08-09 | E-GEOD-76454 | biostudies-arrayexpress

Homo sapiens

Project description:Epigenomic Alterations Define Lethal CIMP-positive Ependymomas of Infancy

| PRJNA193601 | ENA

Homo sapiens

Project description:Epigenomic Alterations Define Lethal CIMP positive Ependymomas of Infancy

| PRJNA241314 | ENA

H3K27ac ChIP-Seq in LOUCY

Project description:H3K27ac ChIP-Seq data of the T-ALL cell line LOUCY was obtained to find active regions in the genome and to correlate that with expression profiling of lncRNAs in the LOUCY cell line. ChIP-sequencing data was generated for H3K27ac in the T-ALL cell line LOUCY.

2016-05-17 | E-GEOD-74311 | biostudies-arrayexpress

ChIP-seq of mouse primary cultured bone marrow-derived neutrophils stimulated by lung cancer cell conditional medium

Project description:Bone marrow-derived neutrophils from C57BL/6J mice were treated with 10% LLC1 conditional medium or normal medium as the control for 2 hours, then processed using the SimpleChIP Enzymatic Chromatin IP Kit according to the manufacturer’s instructions. Antibodies against Smad3 and IgG isotype were used for immunoprecipitation. We performed ChIP-seq for Smad3 immuno-enriched DNA (Input and Smad3-IP) and mapped clean sequences against GRCm38 using Bowtie2, and peaks were identified using model-based analysis for ChIP-Seq (MACS) with default parameters.

2023-03-18 | E-MTAB-12740 | biostudies-arrayexpress

H3K27ac ChIP-Seq in ALL-SIL

Project description:The T-cell leukemia homeobox 1 (TLX1, HOX11) transcription factor is critically involved in the multistep pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanisms by which these T-cell specific oncogenes cooperate during transformation remain to be established. Here, we used an integrative genomics approach to show that the oncogenic properties of TLX1 are mediated by genome-wide interference with the ETS1 and RUNX1 transcription factors. Partial disruption of ETS1 and RUNX1 activity by ectopic TLX1 expression in immature thymocytes drives repression of T-cell specific super-enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 signaling. These phenomena coordinately trigger a TLX1 driven pre-leukemic phenotype in human thymic precursor cells, which corresponds with the in vivo thymic regression observed in murine TLX1 tumor models, and creates a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multistep pathogenesis of TLX1 driven human leukemia. ChIP-sequencing data was generated for H3K27ac in the T-ALL cell line ALL-SIL.

2015-08-05 | E-GEOD-70734 | biostudies-arrayexpress

Chip-seq analysis of hrpRSL and Lon in Pseudomonas syringas

Project description:Pseudomonas syringae uses HrpRSL to regulate the expression of type III secretion system (T3SS) genes and bacterial virulence. However, the molecular mechanism and the regulons of HrpRSL have yet to be fully elucidated. Here, we performed chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) on HrpRSL and Lon. The direct regulation of these genes by corresponding regulator has been confirmed by Electrophoretic mobility shift assays (EMSAs) and quantitative real-time polymerase chain reactions (qRT-PCR). Binding motifs are found by using MEME suite and verified by footprint assays in vitro. Collectively, this work provides new cues to better understand the detailed regulatory networks of T3SS systems in P. syringae. ChIP-seq analysis of HrpRSL and Lon in Pseudomonas syringas

2015-12-31 | E-GEOD-65437 | biostudies-arrayexpress

Chromatin accessibility profiling of developing cerebellar granule neurons identifies novel neuronal enhancers and reveals a role for Zic transcription factors in neuronal maturation

Project description:To identify chromatin mechanisms of neuronal differentiation, we characterized the relationship between chromatin accessibility and gene expression in cerebellar granule neurons (CGNs) of the developing mouse. We used DNase-seq to globally map accessibility of cis-regulatory elements and RNA-seq to profile transcript abundance at key points in postnatal neuronal differentiation in vivo and in culture. We observed thousands of chromatin accessibility changes as CGNs differentiated and determined that many of these regions function as stage-specific neuronal enhancers. Motif discovery within differentially accessible chromatin regions suggested a novel role for the Zic family of transcription factors in CGN maturation, and we confirmed the association of Zic with these elements by ChIP-seq. Knockdown of Zic1 and Zic2 indicated Zic transcription factors are required to coordinate mature neuronal gene expression patterns. These data reveal chromatin dynamics at thousands of gene regulatory elements that facilitate gene expression patterns necessary for neuronal differentiation and function. Biological triplicate DNase-seq and RNA-seq samples from 3 in vivo cerebellum developmental stages (P7, P14, P60) and 3 cultured CGN stages (isolated granule neuron precursors, +3DIV, and +7DIV) obtained. Zic1 and Zic2 were separately knocked down by lentiviral shRNA in cultured CGNs followed by RNA-seq (2 biological replicates per KD and 2 controls). Zic1/2 ChIP-seq was performed with in vivo cerebellum at two developmental stages (P7 and P60) in duplicate with matching input and IgG controls.

2015-02-27 | E-GEOD-60731 | biostudies-arrayexpress

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