Identification of cis-regulatory mutations generating de novo edges in personalized cancer gene regulatory networks
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ABSTRACT:
PROVIDER: EGAS00001002571 | EGA |
REPOSITORIES: EGA
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Project description:The identification of functional non-coding mutations is a key challenge in the field of genomics, where whole-genome re-sequencing can swiftly generate a set of all genomic variants in a sample, such as a tumor biopsy. The size of the human regulatory landscape places a challenge on finding recurrent cis-regulatory mutations across samples of the same cancer type. Therefore, powerful computational approaches are required to sift through the tens of thousands of non-coding variants, to identify potentially functional variants that have an impact on the gene expression profile of the sample. Here we introduce an integrative analysis pipeline, called μ-cisTarget, to filter, annotate and prioritize non-coding variants based on their putative effect on the underlying 'personal' gene regulatory network. We first validate μ-cisTarget by re-analyzing three cases of oncogenic non-coding mutations, namely the TAL1 and LMO1 enhancer mutations in T-ALL, and the TERT promoter mutation in melanoma. Next, we re-sequenced the full genome of ten cancer cell lines of six different cancer types, and used matched transcriptome data and motif discovery to infer master regulators for each sample. We identified candidate functional non-coding mutations that generate de novo binding sites for these master regulators, and that result in the up-regulation of nearby oncogenic drivers. We finally validated the predictions using tertiary data including matched epigenome data. Our approach is generally applicable to re-sequenced cancer genomes, or other genomes, when a disease- or sample-specific gene signature is available for network inference. μ-cisTarget is available from http://mucistarget.aertslab.org.
2017-07-14 | GSE101408 | GEO
Project description:Recent ChIP-chip studies have revealed that many in vivo binding sites have a weak match to the consensus sequence for the transcription factor being analyzed. Possible explanations for these observations include a) the consensus site was derived from in vitro analyses and does not represent the preferred in vivo binding site and/or b) the factor is recruited to a weak binding site via interaction with a protein that binds nearby. To address these possibilities we have developed a motif discovery approach (ChIPMotifs) that incorporates a bootstrap re-sampling method to statistically infer the optimal cutoff threshold for a position weight matrix (PWM) of a motif identified from in vivo ChIP-chip data by ab initio motif discovery programs. Using OCT4 ChIP-chip data derived from genomic tiling arrays and the ChIPMotifs approach, we developed a refined OCT4 PWM. We then used the in vivo-derived PWM and a ChIPModules approach to identify transcription factors co-localizing with OCT4 in a testicular germ cell tumor (Ntera2 cells). We found that the consensus binding site for SRY, a transcription factor critical for testis development, co-localizes with the OCT4 PWM. To further characterize the relationship between OCT4 and SRY binding sites, we used ChIP-chip analysis of human promoter microarrays, and found that 49% of the top ~1000 OCT4 target promoters were also bound by SRY. This analysis represents the first identification of SRY target promoters. Our studies not only validate the ChIPMotifs and ChIPModules combinatorial approach but also identify a possible new regulatory partner of OCT4. Keywords: ChIP-chip, computational approaches
2007-01-25 | GSE6409 | GEO
Project description:The transcriptional programs of ectothermic teleosts are directly influenced by water temperature. Although various cold-responsive transcriptional patterns have been determined in fishes, the systematic molecular networks governing the temperature responses are still unknown. We profiled the transcriptional responses in eight tissues of zebrafish exposed to graded cold temperatures, ranging from normal (28°C) to mild (18°C) and severe (10°C) cold, using RNA-seq. The tissues varied in the number of cold-responsive genes, of which the kidney appeared to be most sensitive, whereas the brain was the least. Fuzzy k-means clustering revealed 34 gene clusters of distinct expression patterns, demonstrating diverse tissue-specific responses in conjunction with multiple aspects of ubiquitous cross-tissue responses to cold. Thirty-one GO terms were over-represented upon cold treatment. These terms are involved in basic cellular processes, such as RNA splicing and proton transport, as well tissue-specific processes, such as ‘negative regulation of endopeptidase activity’ in the kidney. To identify the cis-regulatory elements governing the concerted cold responses, the promoters of the genes that demonstrated strong co-regulation were analyzed using an enriched motif discovery program, DREME. Eleven motifs, 6 known and 5 novel, were identified. These motifs belong to the genes corresponding to the 16 over-represented GO terms identified above. Some motifs, such as the AP-1 and STAT1 binding sites, are known to be stress responsive. By integrating comprehensive cold-induced transcriptional changes with a cis-motif identification tool, we identified genome-wide regulatory networks for the cold response in zebrafish. The identified networks provided new insights into molecular mechanisms of thermal responses in teleosts. Examination of gene expression of 24 samples (eight tissues at three temperatures)
2015-08-06 | E-GEOD-62221 | biostudies-arrayexpress
Project description:Here we derive human and chimpanzee cranial neural crest cells (CNCCs) and profile histone modifications, transcription factors, chromatin accessibility and gene expression to systematically and quantitatively annotate evolutionary divergence of craniofacial cis-regulatory landscapes.
2015-09-11 | GSE70751 | GEO
Project description:Here we derive human and chimpanzee cranial neural crest cells (CNCCs) and profile histone modifications, transcription factors, chromatin accessibility and gene expression to systematically and quantitatively annotate evolutionary divergence of craniofacial cis-regulatory landscapes. Histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K27me3), chromatin modifiers (p300), transcription factors (NR2F1, TFAP2A), chromatin accessibility (ATACseq) and gene expression (RNAseq) were assayed in CNCCs derived from iPSCs/ESCs from 2 chimpanzee and 3 human individuals.
2015-09-11 | E-GEOD-70751 | biostudies-arrayexpress
Project description:The goal of this study is to improve the quality, efficiency, and sustainability of milk production by improving the understanding of the function of cis-regulatory elements in regulating the bovine mammary gland. To this end, we have characterized the non-lactating and lactating mammary gland transcriptomes by whole transcriptome shotgun sequencing (RNA-seq). We will identify cis-regulatory elements in the non-lactating and lactating bovine mammary gland genome-wide. Finally, we will annotate and characterize mammary gland cis-regulatory elements by computational analysis and identify high-resolution genome-wide in vivo footprints of diverse trans-acting-factors (TF), over-represented TF bindings sites and overlapping SNPs.
2021-04-06 | GSE116079 | GEO
Project description:Here we report a highly scalable strategy for unbiased discovery and functional characterization of cis regulatory elements in the genome. These results demonstrate the utility of our cis element discovery strategy and reveal the dual function of gene promoters: they not only initiate transcription of their own genes, but could also control transcription of nearby genes.
2017-04-17 | GSE81026 | GEO
Project description: Not available
| S-EPMC2141820 | biostudies-other
Project description:The transcriptional programs of ectothermic teleosts are directly influenced by water temperature. Although various cold-responsive transcriptional patterns have been determined in fishes, the systematic molecular networks governing the temperature responses are still unknown. We profiled the transcriptional responses in eight tissues of zebrafish exposed to graded cold temperatures, ranging from normal (28°C) to mild (18°C) and severe (10°C) cold, using RNA-seq. The tissues varied in the number of cold-responsive genes, of which the kidney appeared to be most sensitive, whereas the brain was the least. Fuzzy k-means clustering revealed 34 gene clusters of distinct expression patterns, demonstrating diverse tissue-specific responses in conjunction with multiple aspects of ubiquitous cross-tissue responses to cold. Thirty-one GO terms were over-represented upon cold treatment. These terms are involved in basic cellular processes, such as RNA splicing and proton transport, as well tissue-specific processes, such as ‘negative regulation of endopeptidase activity’ in the kidney. To identify the cis-regulatory elements governing the concerted cold responses, the promoters of the genes that demonstrated strong co-regulation were analyzed using an enriched motif discovery program, DREME. Eleven motifs, 6 known and 5 novel, were identified. These motifs belong to the genes corresponding to the 16 over-represented GO terms identified above. Some motifs, such as the AP-1 and STAT1 binding sites, are known to be stress responsive. By integrating comprehensive cold-induced transcriptional changes with a cis-motif identification tool, we identified genome-wide regulatory networks for the cold response in zebrafish. The identified networks provided new insights into molecular mechanisms of thermal responses in teleosts.
2015-08-06 | GSE62221 | GEO
Project description:Precise gene expression is a fundamental aspect of organismal function and depends on the combinatorial interplay of transcription factors (TFs) with cis‐regulatory DNA elements. While much is known about TF function in general, our understanding of their cell type‐specific activities is still poor. To address how widely expressed transcriptional regulators modulate downstream gene activity with high cellular specificity, we have identified binding regions for the Hox TF Deformed (Dfd) in the Drosophila genome. Our analysis of architectural features within Hox cis‐regulatory response elements (HREs) shows that HRE structure is essential for cell type‐specific gene expression. We also find that Dfd and Ultrabithorax (Ubx), another Hox TF specifying different morphological traits, interact with non‐overlapping regions in vivo, despite their similar DNA binding preferences. While Dfd and Ubx HREs exhibit comparable design principles, their motif compositions and motif‐pair associations are distinct, explaining the highly selective interaction of these Hox proteins with the regulatory environment. Thus, our results uncover the regulatory code imprinted in Hox enhancers and elucidate the mechanisms underlying functional specificity of TFs in vivo.
2015-09-29 | GSE73493 | GEO