Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Epigenetic determinants of self-renewal in glioblastoma

ABSTRACT: We over-expressed an epigenetic regulator in a glioblastoma (GBM) primary culture from an adult patient. These GBM cells have cancer stem cell phenotypes, as they have self-renewal properties and tumor initiation potential when transplanted in immunocompromised mice. ATAC-seq was performed on cells over-expressing the epigenetic regulator and control cells expressing EGFP. ATAC-Seq on glioblastoma cells that over-express EGFP or an epigenetic regulator.

ORGANISM(S): Homo sapiens

SUBMITTER: Alexander Murison

PROVIDER: E-GEOD-67633 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.

Gallo Marco M Coutinho Fiona J FJ Vanner Robert J RJ Gayden Tenzin T Mack Stephen C SC Murison Alex A Remke Marc M Li Ren R Takayama Naoya N Desai Kinjal K Lee Lilian L Lan Xiaoyang X Park Nicole I NI Barsyte-Lovejoy Dalia D Smil David D Sturm Dominik D Kushida Michelle M MM Head Renee R Cusimano Michael D MD Bernstein Mark M Clarke Ian D ID Dick John E JE Pfister Stefan M SM Rich Jeremy N JN Arrowsmith Cheryl H CH Taylor Michael D MD Jabado Nada N Bazett-Jones David P DP Lupien Mathieu M Dirks Peter B PB

Cancer cell 20151125 6

Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing prop ...[more]

PMID: 26626085

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Project description:Objective: Although glucagon-secreting Î±-cells and insulin-secreting Î²-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and have overlaps in their transcriptome and epigenome profiles. Notably, destruction of one of these cell populations can stimulate repopulation via transdifferentiation of the other cell type, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both Î±- and Î²-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and Î²-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in Î±- and Î²-cell specification and plasticity. Methods: We sorted human a- and b-cells and performed the â??Assay for Transposase-Accessible Chromatin with high throughput sequencingâ?? (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions. Results: We identified numerous transcripts with either Î±-cell- or Î²-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The â??group specific proteinâ?? (GC; or vitamin D binding protein) was restricted to a-cells, while CHODL (chondrolectin) immunoreactivity was only present in b-cells. Furthermore, Î±-cell- and Î²-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with common single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes. Conclusions: We have determined the genetic landscape of human Î±- and Î²-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel Î±- and Î²-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion. ATAC-seq on 3 human alpha cell samples, 3 human beta cell samples, and 2 human acinar cell samples. RNA-seq on 7 human alpha cell samples and 8 human beta cell samples.

Dataset Information

Epigenetic determinants of self-renewal in glioblastoma

Publications

MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.

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