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Altered patterns of hydroxymethylation regulate oncogenic pathways in pancreatic cancer

ABSTRACT: Transcriptional deregulation of oncogenic pathways is a hallmark of cancer, and can be due to epigenetic alterations. 5-hydroxymethylcytosine is a recently discovered epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC enriched loci was conducted in low-passage pancreatic cancer cell lines and primary patient-derived xenografts and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected regulatory regions of the genome, specifically overlapping with H3K4me1 enhancers. Gain of 5-hmC was correlated with upregulation of the cognate transcripts, including many oncogenic pathways implicated in pancreatic neoplasia. Specifically, BRD4 was overexpressed and acquired 5hmC at enhancer regions in majority of neoplastic samples. Functionally, acquisition of 5hmC at BRD4 promoter regulated increase in transcript expression. Furthermore, blockade of BRD4 inhibited pancreatic cancer growth in vivo. In summary, redistribution of 5-hmC and preferential enrichment at oncogenic enhancers is a novel regulatory mechanism in human cancer. Genome-wide analysis of 5-hmC enriched loci was conducted in low-passage pancreatic cancer cell lines and primary patient-derived xenografts

ORGANISM(S): Homo sapiens

SUBMITTER: Yiting Yu

PROVIDER: E-GEOD-71839 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Altered patterns of hydroxymethylation regulate oncogenic pathways in pancreatic cancer

Project description:Transcriptional deregulation of oncogenic pathways is a hallmark of cancer, and can be due to epigenetic alterations. 5-hydroxymethylcytosine is a recently discovered epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC enriched loci was conducted in low-passage pancreatic cancer cell lines and primary patient-derived xenografts and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected regulatory regions of the genome, specifically overlapping with H3K4me1 enhancers. Gain of 5-hmC was correlated with upregulation of the cognate transcripts, including many oncogenic pathways implicated in pancreatic neoplasia. Specifically, BRD4 was overexpressed and acquired 5hmC at enhancer regions in majority of neoplastic samples. Functionally, acquisition of 5hmC at BRD4 promoter regulated increase in transcript expression. Furthermore, blockade of BRD4 inhibited pancreatic cancer growth in vivo. In summary, redistribution of 5-hmC and preferential enrichment at oncogenic enhancers is a novel regulatory mechanism in human cancer.

2016-08-06 | GSE71839 | GEO

Altered Hydroxymethylation is seen at regulatory regions in pancreatic cancer and regulates oncogenic pathways [MeDIP-seq]

Project description:Transcriptional deregulation of oncogenic pathways is a hallmark of cancer, and can be due to epigenetic alterations. 5-hydroxymethylcytosine is a recently discovered epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC enriched loci with hmC-seal was conducted in low-passage pancreatic cancer cell lines and primary patient-derived xenografts and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers. Furthermore, base pair resolution analysis of methylation and hydroxymethylation with oxidative bisulfite sequencing was conducted and correlated with chromatin accessibility by ATAC-seq in pancreatic cancer and control samples. 5hmC was specifically enriched at open regions of chromatin and gain of 5-hmC was correlated with upregulation of the cognate transcripts, including many oncogenic pathways implicated in pancreatic neoplasia, such as myc, KRAS, VEGF and BRD4. Specifically, BRD4 was overexpressed and acquired 5hmC at enhancer regions in majority of neoplastic samples. Functionally, acquisition of 5hmC at BRD4 promoter regulated increase in transcript expression. Furthermore, blockade of BRD4 inhibited pancreatic cancer growth in vivo. In summary, redistribution of 5-hmC and preferential enrichment at oncogenic enhancers is a novel regulatory mechanism in human cancer.

2017-09-14 | GSE97014 | GEO

Altered Hydroxymethylation is seen at regulatory regions in pancreatic cancer and regulates oncogenic pathways [RNA-seq]

Project description:Transcriptional deregulation of oncogenic pathways is a hallmark of cancer, and can be due to epigenetic alterations. 5-hydroxymethylcytosine is a recently discovered epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC enriched loci with hmC-seal was conducted in low-passage pancreatic cancer cell lines and primary patient-derived xenografts and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers. Furthermore, base pair resolution analysis of methylation and hydroxymethylation with oxidative bisulfite sequencing was conducted and correlated with chromatin accessibility by ATAC-seq in pancreatic cancer and control samples. 5hmC was specifically enriched at open regions of chromatin and gain of 5-hmC was correlated with upregulation of the cognate transcripts, including many oncogenic pathways implicated in pancreatic neoplasia, such as myc, KRAS, VEGF and BRD4. Specifically, BRD4 was overexpressed and acquired 5hmC at enhancer regions in majority of neoplastic samples. Functionally, acquisition of 5hmC at BRD4 promoter regulated increase in transcript expression. Furthermore, blockade of BRD4 inhibited pancreatic cancer growth in vivo. In summary, redistribution of 5-hmC and preferential enrichment at oncogenic enhancers is a novel regulatory mechanism in human cancer.

2017-09-14 | GSE97003 | GEO

Altered Hydroxymethylation is seen at regulatory regions in pancreatic cancer and regulates oncogenic pathways [ATAC-seq]

Project description:Transcriptional deregulation of oncogenic pathways is a hallmark of cancer, and can be due to epigenetic alterations. 5-hydroxymethylcytosine is a recently discovered epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC enriched loci with hmC-seal was conducted in low-passage pancreatic cancer cell lines and primary patient-derived xenografts and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers. Furthermore, base pair resolution analysis of methylation and hydroxymethylation with oxidative bisulfite sequencing was conducted and correlated with chromatin accessibility by ATAC-seq in pancreatic cancer and control samples. 5hmC was specifically enriched at open regions of chromatin and gain of 5-hmC was correlated with upregulation of the cognate transcripts, including many oncogenic pathways implicated in pancreatic neoplasia, such as myc, KRAS, VEGF and BRD4. Specifically, BRD4 was overexpressed and acquired 5hmC at enhancer regions in majority of neoplastic samples. Functionally, acquisition of 5hmC at BRD4 promoter regulated increase in transcript expression. Furthermore, blockade of BRD4 inhibited pancreatic cancer growth in vivo. In summary, redistribution of 5-hmC and preferential enrichment at oncogenic enhancers is a novel regulatory mechanism in human cancer.

2017-09-14 | GSE97008 | GEO

Genome wide hydroxymethylation tested using the HELP-GT assay shows redistribution in cancer

Project description:Background: 5-hydroxymethylcytosine (5-hmC) is a recently discovered epigenetic modification that is altered in cancers. Genome wide assays for 5-hmC determination are needed as many of the techniques commonly used to assay 5-methylcytosine (5-mC), including conventional methyl-sensitive restriction digest and bisulfite sequencing, are incapable of distinguishing between 5-mC and 5-hmC. Results: Glycosylation of 5-hmC residues by beta-Glucosyl Transferase (beta-GT) can make CCGG residues insensitive to digestion by MspI. We used this premise to modify the HELP-tagging assay to identify both 5-mC and 5-hmC loci in the genome. Comparison of sequencing libraries after HpaII, MspI and MspI+ beta-GT conversion resulted in locus specific 5-mC and 5-hmC determination. A custom bioinformatics pipeline was created to identify 5-hmC sites that were validated at global level by LS-MS and the locus specific level by qRT-PCR of 5-hmC pulldown DNA. Hydroxymethylation at both promoter and intragenic locations correlated positively with gene expression. Analysis of pancreatic cancer samples revealed striking redistribution of 5-hmC sites in cancer cells and demonstrated enrichment of this modification at many oncogenic promoters such as GATA6. Conclusions: The HELP-GT assay allows a high resolution, simultaneous determination of 5-hmC and 5-mC loci from small amounts of DNA with the utilisation of modest sequencing resources. Redistribution of 5-hmC seen in cancer highlights the importance of examining this modification in conjugation with conventional methylome analysis. We did methylation and hydroxymethylation tests for one control and two pancreatic cancer cases

2013-07-30 | E-GEOD-42723 | biostudies-arrayexpress

YAP conveys an invasive phenotype to clear cell renal cell carcinoma cell lines via endothelin-2

Project description:To determine the biological mechanisms underlying the oncogenic properties of YAP in ccRCC the human ccRCC cell line MZ1774 was transduced with lentivirus containing a shRNA-cassette targeting YAP-mRNA. Expression profiles of MZ1774 YAP knockdown cells were compared to mock-transduced control cells. Total RNA from MZ1774 cells stably expressing shRNA directed against YAP compared to mock-transduced MZ1174 cells

2014-12-23 | E-GEOD-50053 | biostudies-arrayexpress

Genome wide hydroxymethylation tested using the HELP-GT assay shows redistribution in cancer

2013-07-30 | GSE42723 | GEO

Proteogenomic Network Analysis of Context-Specific KRAS Signaling In Mouse-to-Human Cross-Species Translation

Project description:The highest frequencies of KRAS mutations occur in colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC). Therapeutically targeting downstream pathways mediating oncogenic properties of KRAS mutant cancers is limited by an incomplete understanding of the contextual cues modulating the signaling output of activated KRAS. We performed mass spectrometry on mouse tissues expressing wild-type or mutant KRAS to determine how tissue context and genetic background modulate oncogenic signaling. Mutant KRAS dramatically altered the proteomes and phosphoproteomes of pre-neoplastic and neoplastic colons and pancreases in a largely context-specific manner. We developed an approach to humanize the mouse networks with data from human cancer and identified genes within the CRC and PDAC networks synthetically lethal with mutant KRAS. Our studies demonstrate the context-dependent plasticity of oncogenic signaling, identify non-canonical mediators of KRAS oncogenicity within the KRAS-regulated signaling network, and demonstrate how statistical integration of mouse and human datasets can reveal cross-species therapeutic insights.

2019-06-28 | PXD013922 | Pride

IP of 5-methylcytosine (5-hmC) enriched DNA fragments from control and PB treated mouse livers (1 day)

Project description:5-hmC is an epigenetic modification of the DNA base cytosine with roles in gene silencing events, imprinting and X inactivation. Phenobarbital (PB) is a well studied non-genotoxic carcinogen with roles in epigenetic perturbation. We profile 5hmC in both control mouse livers as well as in the livers of 1 day PB treated mice. 5hmC is largely found to reside in the bodies of active genes and promoter levels are perturbed upon PB induced gene activation events. 5-hmC is assocated with promoters fo silent genes. Upon PB exposire a handfull of genes are induced which reveal decreases in promoter 5hmC levels comparison of 5-hmC profiles in 5 control and 5 PB exposed mouse livers (dose: 1day PB)

2012-11-10 | E-GEOD-41395 | biostudies-arrayexpress

IP of 5-methylcytosine (5-hmC) enriched DNA fragments from control and PB treated mouse livers (91 day)

Project description:5-hmC is an epigenetic modification of the DNA base cytosine with roles in gene silencing events, imprinting and X inactivation. Phenobarbital (PB) is a well studied non-genotoxic carcinogen with roles in epigenetic perturbation. We profile 5hmC in both control mouse livers as well as in the livers of 91 day PB treated mice. 5hmC is largely found to reside in the bodies of active genes and promoter levels are perturbed upon PB induced gene activation events. 5-hmC is assocated with promoters fo silent genes. Upon PB exposire a handfull of genes are induced which reveal decreases in promoter 5hmC levels comparison of 5-hmC profiles in 5 control and 5 PB exposed mouse livers (dose: 91day PB)

2012-11-10 | E-GEOD-41397 | biostudies-arrayexpress

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