Unknown,Transcriptomics,Genomics,Proteomics

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Comprehensive nucleosome mapping of the human genome in cancer progression

ABSTRACT: Altered chromatin structure is a hallmark of cancer, and inappropriate regulation of chromatin structure may represent the origin of transformation. Several important studies have mapped human nucleosome distributions genome wide, but the genome-wide role of chromatin structure in cancer progression has not been addressed. We developed a MNase-Sequence Capture method, mTSS-seq, to map genome-wide nucleosome distribution in primary human lung and colon adenocarcinoma tissue. Here, we confirm that nucleosome redistribution is an early, widespread event in lung (LAC) and colon (CRC) adenocarcinoma. These altered nucleosome architectures are consistent between LAC and CRC patient samples indicating that they may serve as important early adenocarcinoma markers. We demonstrate that the nucleosome alterations are driven by the underlying DNA sequence and potentiate transcription factor binding. We conclude that DNA-directed nucleosome redistributions are widespread early in cancer progression. We have proposed an entirely new hierarchical model for chromatin-mediated genome regulation. â Nucleosome distribution mapping in primary patient tissue at all transcription start sites in the human genome Please note that two processed data files '4137N_ALLcombined.bed' and '4137T_ALLcombined.bed' (linked as Series supplementary file) are processed bed files combined from three 4137N_*_hiseq samples (total 6 raw data files) and three 4137T_*_hiseq samples (total 6 raw data files), respectively.

ORGANISM(S): Homo sapiens

SUBMITTER: Brooke Druliner

PROVIDER: E-GEOD-74340 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Distant enhancer elements are a major source of specificity in mammalian gene expression. Although enhancers that regulate broad developmental decisions and inducible gene expression have been studied extensively, little is known about regulatory elements that govern monogenic and monoallelic expression. Here, using high throughput epigenetic and genetic techniques we identified a plethora of distant enhancers that regulate monoallelic olfactory receptor (OR) gene expression. Potential OR enhancers have unique, cell type specific epigenetic marks that distinguish them from other neuronal enhancers and correlate with enhancer activity in vivo. Using sequence capture to enrich for these sequences we identified Dnase-protected footprints that reveal novel regulatory sequences and transcription factors required for OR gene activation. Our experiments provide insight to the regulation of OR expression, and describe novel principles and methodologies towards the understanding of transcriptional mechanisms that generate cellular diversity. In vivo examination of H3K79me3 enrichment and DNAse protected footprints on olfactory receptor enhancer sequences. We performed ChIP-seq on native chromatin isolated from the mouse olfactory epithelium using antibodies against H3K79me3. To sequence accessible regions of the genome we treated nuclei with limiting amounts of DNAse I to digest accessible chromatin and perform Dnase Hypersensitivity (DHS)-seq. In the olfactory epithelium, the H enhancer – the first described enhancer for olfactory receptors has a well-defined DNAse I hypersensitivity peak and is flanked by high levels of H3K79me3. We find other intergenic sequences nearby olfactory receptor genes that share the same chromatin signature, and test their function in vivo. TO uncover transcription factor footprints on olfactory receptor enhancers we performed sequence capture of the DHS-seq library to enrich for these sequences. We find multiple DNAse-protected sequences and perform motif analysis on transcription factor footprints to reveal factors involved in olfactory receptor gene regulation.

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Comprehensive nucleosome mapping of the human genome in cancer progression

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