title: Inferring regulatory element landscapes and transcription factor networks from cancer methylomes.
abstract: Recent studies indicate that DNA methylation can be used to identify transcriptional enhancers, but no systematic approach has been developed for genome-wide identification and analysis of enhancers based on DNA methylation. We describe ELMER (Enhancer Linking by Methylation/Expression Relationships), an R-based tool that uses DNA methylation to identify enhancers and correlates enhancer state with expression of nearby genes to identify transcriptional targets. Transcription factor motif analysis of enhancers is coupled with expression analysis of transcription factors to infer upstream regulators. Using ELMER, we investigated more than 2,000 tumor samples from The Cancer Genome Atlas. We identified networks regulated by known cancer drivers such as GATA3 and FOXA1 (breast cancer), SOX17 and FOXA2 (endometrial cancer), and NFE2L2, SOX2, and TP63 (squamous cell lung cancer). We also identified novel networks with prognostic associations, including RUNX1 in kidney cancer. We propose ELMER as a powerful new paradigm for understanding the cis-regulatory interface between cancer-associated transcription factors and their functional target genes.
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1450 Biggy Street, NRT 6503, Los Angeles, CA, 90089-9601, USA. lijingya@usc.edu.
authors.forename: Lijing
authors.initials: L
authors.lastname: Yao
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA. Hui.Shen@vai.org.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA. Peter.Laird@vai.org.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1450 Biggy Street, NRT 6503, Los Angeles, CA, 90089-9601, USA. peggy.farnham@med.usc.edu.
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: Farnham
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1450 Biggy Street, NRT 6503, Los Angeles, CA, 90089-9601, USA. benjamin.berman@cshs.org.|Bioinformatics and Computational Biology Research Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center, AHSP Bldg., Suite A8111, Los Angeles, CA, 90048, USA. benjamin.berman@cshs.org.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Berman
mesh_terms: D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D019175:DNA Methylation; D030541:Databases, Genetic; D004742:Enhancer Elements, Genetic; D050990:GATA3 Transcription Factor / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053263:Gene Regulatory Networks; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000235:genetics; D055760:SOXF Transcription Factors / Q000235:genetics; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009363:Neoplasm Proteins; C493728:RUNX1 protein, human; C109188:SOX17 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D055760:SOXF Transcription Factors; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C040044:neoplasm-associated factor; D051542:Hepatocyte Nuclear Factor 3-beta