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Chromatin run-on and sequencing maps the transcriptional regulatory landscape of glioblastoma multiforme.

ABSTRACT: The human genome encodes a variety of poorly understood RNA species that remain challenging to identify using existing genomic tools. We developed chromatin run-on and sequencing (ChRO-seq) to map the location of RNA polymerase for almost any input sample, including samples with degraded RNA that are intractable to RNA sequencing. We used ChRO-seq to map nascent transcription in primary human glioblastoma (GBM) brain tumors. Enhancers identified in primary GBMs resemble open chromatin in the normal human brain. Rare enhancers that are activated in malignant tissue drive regulatory programs similar to the developing nervous system. We identified enhancers that regulate groups of genes that are characteristic of each known GBM subtype and transcription factors that drive them. Finally we discovered a core group of transcription factors that control the expression of genes associated with clinical outcomes. This study characterizes the transcriptional landscape of GBM and introduces ChRO-seq as a method to map regulatory programs that contribute to complex diseases.

SUBMITTER: Chu T

PROVIDER: S-EPMC6204104 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Chromatin run-on and sequencing maps the transcriptional regulatory landscape of glioblastoma multiforme.

Chu Tinyi T Rice Edward J EJ Booth Gregory T GT Salamanca H Hans HH Wang Zhong Z Core Leighton J LJ Longo Sharon L SL Corona Robert J RJ Chin Lawrence S LS Lis John T JT Kwak Hojoong H Danko Charles G CG

Nature genetics 20181022 11

The human genome encodes a variety of poorly understood RNA species that remain challenging to identify using existing genomic tools. We developed chromatin run-on and sequencing (ChRO-seq) to map the location of RNA polymerase for almost any input sample, including samples with degraded RNA that are intractable to RNA sequencing. We used ChRO-seq to map nascent transcription in primary human glioblastoma (GBM) brain tumors. Enhancers identified in primary GBMs resemble open chromatin in the nor ...[more]

PMID: 30349114

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Project description:Background: Glioblastoma multiforme (GBM), the most common and aggressive human malignant brain tumor, is notorious for its limited treatment options and poor prognosis. MicroRNAs (miRNAs) are found to be involved in tumorigenesis of GBM. However, a comprehensive miRNA-mRNA regulatory network has still not been established. Methods: A miRNA microarray dataset (GSE90603) was obtained from GEO database. Then, we employed GEO2R tool to perform differential expression analysis. Potential transcription factors and target genes of screened differentially expressed miRNAs (DE-miRNAs) were predicted. The GBM mRNA dataset were downloaded from TCGA database for identifying differentially expressed genes (DEGs). Next, GO annotation and KEGG pathway enrichment analysis was conducted. PPI network was then established, and hub genes were identified via Cytoscape software. The expression and prognostic roles of hub genes was further evaluated. Results: Total 33 DE-miRNAs, consisting of 10 upregulated DE-miRNAs and 23 downregulated DE-miRNAs, were screened. SP1 was predicted to potentially regulate most of screened DE-miRNAs. Three thousand and twenty seven and 3,879 predicted target genes were obtained for upregulated and downregulated DE-miRNAs, respectively. Subsequently, 1,715 upregulated DEGs and 1,259 downregulated DEGs were identified. Then, 149 and 295 potential downregulated and upregulated genes commonly appeared in target genes of DE-miRNAs and DEGs were selected for GO annotation and KEGG pathway enrichment analysis. The downregulated genes were significantly enriched in cGMP-PKG signaling pathway and calcium signaling pathway whereas the upregulated genes were enriched in pathways in cancer and PI3K-Akt signaling pathway. Construction and analysis of PPI network showed that STXBP1 and TP53 were recognized as hub genes with the highest connectivity degrees. Expression analytic result of the top 20 hub genes in GBM using GEPIA database was generally identical with previous differential expression analysis for TCGA data. EGFR, PPP3CB, and MYO5A expression was significantly associated with patients' OS. Conclusions: In this study, we established a potential GBM-related miRNA-mRNA regulatory network, which explores a comprehensive understanding of the molecular mechanisms and provides key clues in seeking novel therapeutic targets for GBM. In the future, more experiments need to be performed to validate our current findings.

Project description:BackgroundGlioblastoma multiforme is the most common and aggressive primary adult brain neoplasm. The current standard of care is maximal safe surgical resection, radiotherapy with concomitant temozolomide, followed by adjuvant temozolomide according to the Stupp protocol. Although the protocol is well adopted in high-income countries (HICs), little is known about its adoption in low- and middle-income countries (LMICs). The aim of this study is to describe a protocol design for a systematic review of published studies outlining the differences in GBM management between HICs and LMICs.MethodsA systematic review will be conducted. MedLine via Ovid, Embase and Global Index Medicus will be searched from inception to date in order to identify the relevant studies. Adult patients (>18 years) with histologically confirmed primary unifocal GBM will be included. Surgical and chemoradiation management of GBM tumours will be considered. Commentaries, original research, non-peer reviewed pieces, opinion pieces, editorials and case reports will be included.ResultsPrimary outcomes will include rates of complications, disability-adjusted life years (DALYs), prognosis, progression-free survival (PFS), overall survival (OS) as well as rate of care abandonment and delay. Secondary outcomes will include the presence of neuro-oncology subspecialty training programs.DiscussionThis systematic review will be the first to compare the current landscape of GBM management in HICs and LMICs, highlighting pertinent themes that may be used to optimise treatment in both financial brackets.Systematic review registrationThe protocol has been registered on the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42020215843).HighlightsGlioblastoma multiforme (GBM) remains the most common primary adult cerebral neoplasm, with an age-adjusted incidence rate of 3.22 per 100,000 population and a 5-year survival rate of 6.8%Despite the well-evidenced efficacy of Stupp protocol, the implementation of this approach bears an institutional and individual financial burden that is particularly notable in low- and middle-income countries (LMICs)This systematic review will be the first to compare the current landscape of GBM management in HICs and LMICs, highlighting pertinent themes that may be used to optimise treatment in both financial brackets.

Dataset Information

Chromatin run-on and sequencing maps the transcriptional regulatory landscape of glioblastoma multiforme.

Publications

Chromatin run-on and sequencing maps the transcriptional regulatory landscape of glioblastoma multiforme.

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