Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer

Emily L. Flam, Ludmila Danilova, Dylan Z. Kelley, Elena Stavrovskaya, Theresa Guo, Michael Considine, Jiang Qian, Joseph A. Califano, Alexander Favorov, Elana J. Fertig, Daria A. Gaykalova

Research output: Contribution to journalArticle

Abstract

Current literature suggests that epigenetically regulated super-enhancers (SEs) are drivers of aberrant gene expression in cancers. Many tumor types are still missing chromatin data to define cancer-specific SEs and their role in carcinogenesis. In this work, we develop a simple pipeline, which can utilize chromatin data from etiologically similar tumors to discover tissue-specific SEs and their target genes using gene expression and DNA methylation data. As an example, we applied our pipeline to human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV + OPSCC). This tumor type is characterized by abundant gene expression changes, which cannot be explained by genetic alterations alone. Chromatin data are still limited for this disease, so we used 3627 SE elements from public domain data for closely related tissues, including normal and tumor lung, and cervical cancer cell lines. We integrated the available DNA methylation and gene expression data for HPV + OPSCC samples to filter the candidate SEs to identify functional SEs and their affected targets, which are essential for cancer development. Overall, we found 159 differentially methylated SEs, including 87 SEs that actively regulate expression of 150 nearby genes (211 SE-gene pairs) in HPV + OPSCC. Of these, 132 SE-gene pairs were validated in a related TCGA cohort. Pathway analysis revealed that the SE-regulated genes were associated with pathways known to regulate nasopharyngeal, breast, melanoma, and bladder carcinogenesis and are regulated by the epigenetic landscape in those cancers. Thus, we propose that gene expression in HPV + OPSCC may be controlled by epigenetic alterations in SE elements, which are common between related tissues. Our pipeline can utilize a diversity of data inputs and can be further adapted to SE analysis of diseased and non-diseased tissues from different organisms.

Original languageEnglish (US)
Article number15034
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Gene Expression
Neoplasms
Chromatin
Genes
DNA Methylation
Epigenomics
Carcinogenesis
Public Sector
Uterine Cervical Neoplasms
Squamous Cell Carcinoma
Melanoma
Lung Neoplasms
Urinary Bladder
Breast
Cell Line

ASJC Scopus subject areas

  • General

Cite this

Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer. / Flam, Emily L.; Danilova, Ludmila; Kelley, Dylan Z.; Stavrovskaya, Elena; Guo, Theresa; Considine, Michael; Qian, Jiang; Califano, Joseph A.; Favorov, Alexander; Fertig, Elana J.; Gaykalova, Daria A.

In: Scientific reports, Vol. 9, No. 1, 15034, 01.12.2019.

Research output: Contribution to journalArticle

Flam, Emily L. ; Danilova, Ludmila ; Kelley, Dylan Z. ; Stavrovskaya, Elena ; Guo, Theresa ; Considine, Michael ; Qian, Jiang ; Califano, Joseph A. ; Favorov, Alexander ; Fertig, Elana J. ; Gaykalova, Daria A. / Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer. In: Scientific reports. 2019 ; Vol. 9, No. 1.
@article{e8e1cc792b38496d9c6795b91d4bddc2,
title = "Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer",
abstract = "Current literature suggests that epigenetically regulated super-enhancers (SEs) are drivers of aberrant gene expression in cancers. Many tumor types are still missing chromatin data to define cancer-specific SEs and their role in carcinogenesis. In this work, we develop a simple pipeline, which can utilize chromatin data from etiologically similar tumors to discover tissue-specific SEs and their target genes using gene expression and DNA methylation data. As an example, we applied our pipeline to human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV + OPSCC). This tumor type is characterized by abundant gene expression changes, which cannot be explained by genetic alterations alone. Chromatin data are still limited for this disease, so we used 3627 SE elements from public domain data for closely related tissues, including normal and tumor lung, and cervical cancer cell lines. We integrated the available DNA methylation and gene expression data for HPV + OPSCC samples to filter the candidate SEs to identify functional SEs and their affected targets, which are essential for cancer development. Overall, we found 159 differentially methylated SEs, including 87 SEs that actively regulate expression of 150 nearby genes (211 SE-gene pairs) in HPV + OPSCC. Of these, 132 SE-gene pairs were validated in a related TCGA cohort. Pathway analysis revealed that the SE-regulated genes were associated with pathways known to regulate nasopharyngeal, breast, melanoma, and bladder carcinogenesis and are regulated by the epigenetic landscape in those cancers. Thus, we propose that gene expression in HPV + OPSCC may be controlled by epigenetic alterations in SE elements, which are common between related tissues. Our pipeline can utilize a diversity of data inputs and can be further adapted to SE analysis of diseased and non-diseased tissues from different organisms.",
author = "Flam, {Emily L.} and Ludmila Danilova and Kelley, {Dylan Z.} and Elena Stavrovskaya and Theresa Guo and Michael Considine and Jiang Qian and Califano, {Joseph A.} and Alexander Favorov and Fertig, {Elana J.} and Gaykalova, {Daria A.}",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-51018-x",
language = "English (US)",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer

AU - Flam, Emily L.

AU - Danilova, Ludmila

AU - Kelley, Dylan Z.

AU - Stavrovskaya, Elena

AU - Guo, Theresa

AU - Considine, Michael

AU - Qian, Jiang

AU - Califano, Joseph A.

AU - Favorov, Alexander

AU - Fertig, Elana J.

AU - Gaykalova, Daria A.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Current literature suggests that epigenetically regulated super-enhancers (SEs) are drivers of aberrant gene expression in cancers. Many tumor types are still missing chromatin data to define cancer-specific SEs and their role in carcinogenesis. In this work, we develop a simple pipeline, which can utilize chromatin data from etiologically similar tumors to discover tissue-specific SEs and their target genes using gene expression and DNA methylation data. As an example, we applied our pipeline to human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV + OPSCC). This tumor type is characterized by abundant gene expression changes, which cannot be explained by genetic alterations alone. Chromatin data are still limited for this disease, so we used 3627 SE elements from public domain data for closely related tissues, including normal and tumor lung, and cervical cancer cell lines. We integrated the available DNA methylation and gene expression data for HPV + OPSCC samples to filter the candidate SEs to identify functional SEs and their affected targets, which are essential for cancer development. Overall, we found 159 differentially methylated SEs, including 87 SEs that actively regulate expression of 150 nearby genes (211 SE-gene pairs) in HPV + OPSCC. Of these, 132 SE-gene pairs were validated in a related TCGA cohort. Pathway analysis revealed that the SE-regulated genes were associated with pathways known to regulate nasopharyngeal, breast, melanoma, and bladder carcinogenesis and are regulated by the epigenetic landscape in those cancers. Thus, we propose that gene expression in HPV + OPSCC may be controlled by epigenetic alterations in SE elements, which are common between related tissues. Our pipeline can utilize a diversity of data inputs and can be further adapted to SE analysis of diseased and non-diseased tissues from different organisms.

AB - Current literature suggests that epigenetically regulated super-enhancers (SEs) are drivers of aberrant gene expression in cancers. Many tumor types are still missing chromatin data to define cancer-specific SEs and their role in carcinogenesis. In this work, we develop a simple pipeline, which can utilize chromatin data from etiologically similar tumors to discover tissue-specific SEs and their target genes using gene expression and DNA methylation data. As an example, we applied our pipeline to human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV + OPSCC). This tumor type is characterized by abundant gene expression changes, which cannot be explained by genetic alterations alone. Chromatin data are still limited for this disease, so we used 3627 SE elements from public domain data for closely related tissues, including normal and tumor lung, and cervical cancer cell lines. We integrated the available DNA methylation and gene expression data for HPV + OPSCC samples to filter the candidate SEs to identify functional SEs and their affected targets, which are essential for cancer development. Overall, we found 159 differentially methylated SEs, including 87 SEs that actively regulate expression of 150 nearby genes (211 SE-gene pairs) in HPV + OPSCC. Of these, 132 SE-gene pairs were validated in a related TCGA cohort. Pathway analysis revealed that the SE-regulated genes were associated with pathways known to regulate nasopharyngeal, breast, melanoma, and bladder carcinogenesis and are regulated by the epigenetic landscape in those cancers. Thus, we propose that gene expression in HPV + OPSCC may be controlled by epigenetic alterations in SE elements, which are common between related tissues. Our pipeline can utilize a diversity of data inputs and can be further adapted to SE analysis of diseased and non-diseased tissues from different organisms.

UR - http://www.scopus.com/inward/record.url?scp=85073656820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073656820&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-51018-x

DO - 10.1038/s41598-019-51018-x

M3 - Article

C2 - 31636280

AN - SCOPUS:85073656820

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 15034

ER -