Journal Article
. 2015 May; 16:105.
doi: 10.1186/s13059-015-0668-3.

Inferring regulatory element landscapes and transcription factor networks from cancer methylomes

Lijing Yao 1 Hui Shen 2 Peter W Laird 3 Peggy J Farnham 4 Benjamin P Berman 5 
Affiliations
  • PMID: 25994056
  •     85 References
  •     61 citations

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.

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Peng Wang, San-Pin Wu, +4 authors, Thomas E Spencer.
Endocrinology, 2018 Mar 17; 159(4). PMID: 29546371    Free PMC article.
Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.
Tathiane M Malta, Artem Sokolov, +21 authors, Maciej Wiznerowicz.
Cell, 2018 Apr 07; 173(2). PMID: 29625051    Free PMC article.
Highly Cited.
Integrative (epi) Genomic Analysis to Predict Response to Androgen-Deprivation Therapy in Prostate Cancer.
Sukanya Panja, Sheida Hayati, +2 authors, Antonina Mitrofanova.
EBioMedicine, 2018 Apr 25; 31. PMID: 29685789    Free PMC article.
Mut2Vec: distributed representation of cancerous mutations.
Sunkyu Kim, Heewon Lee, Keonwoo Kim, Jaewoo Kang.
BMC Med Genomics, 2018 Apr 27; 11(Suppl 2). PMID: 29697361    Free PMC article.
MICMIC: identification of DNA methylation of distal regulatory regions with causal effects on tumorigenesis.
Yin Tong, Jianlong Sun, +6 authors, Jiangwen Zhang.
Genome Biol, 2018 Jun 07; 19(1). PMID: 29871649    Free PMC article.
Computational Biology Solutions to Identify Enhancers-target Gene Pairs.
Judith Mary Hariprakash, Francesco Ferrari.
Comput Struct Biotechnol J, 2019 Jul 19; 17. PMID: 31316726    Free PMC article.
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Genome-wide analysis of aberrant methylation of enhancer DNA in human osteoarthritis.
Xiaozong Lin, Li Li, +4 authors, Limei Wang.
BMC Med Genomics, 2020 Jan 05; 13(1). PMID: 31900157    Free PMC article.
Epigenetic and Transcriptomic Characterization of Pure Adipocyte Fractions From Obese Pigs Identifies Candidate Pathways Controlling Metabolism.
Mette Juul Jacobsen, Jakob H Havgaard, +12 authors, Romain Barrès.
Front Genet, 2020 Jan 11; 10. PMID: 31921306    Free PMC article.
Integrated Epigenome, Exome, and Transcriptome Analyses Reveal Molecular Subtypes and Homeotic Transformation in Uterine Fibroids.
Jitu Wilson George, Huihui Fan, +12 authors, Jose Manuel Teixeira.
Cell Rep, 2019 Dec 19; 29(12). PMID: 31851934    Free PMC article.
Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity.
Luca Fagnocchi, Vittoria Poli, Alessio Zippo.
Cell Mol Life Sci, 2018 Apr 25; 75(14). PMID: 29691590
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DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.
H Binder, E Willscher, +21 authors, M Loeffler.
Acta Neuropathol Commun, 2019 Apr 27; 7(1). PMID: 31023364    Free PMC article.
Collective effects of long-range DNA methylations predict gene expressions and estimate phenotypes in cancer.
Soyeon Kim, Hyun Jung Park, Xiangqin Cui, Degui Zhi.
Sci Rep, 2020 Mar 05; 10(1). PMID: 32127627    Free PMC article.
Integrative analysis of DNA methylation-driven genes for the prognosis of lung squamous cell carcinoma using MethylMix.
Rui Li, Yun-Hong Yin, +4 authors, Yi-Qing Qu.
Int J Med Sci, 2020 Mar 29; 17(6). PMID: 32218699    Free PMC article.
Exploring 3D chromatin contacts in gene regulation: The evolution of approaches for the identification of functional enhancer-promoter interaction.
Hang Xu, Shijie Zhang, +2 authors, Mulin Jun Li.
Comput Struct Biotechnol J, 2020 Apr 01; 18. PMID: 32226593    Free PMC article.
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Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer.
Naveen Ravi, Minjun Yang, +2 authors, Kajsa Paulsson.
Cancers (Basel), 2020 Mar 19; 12(3). PMID: 32183222    Free PMC article.
ELMER v.2: an R/Bioconductor package to reconstruct gene regulatory networks from DNA methylation and transcriptome profiles.
Tiago C Silva, Simon G Coetzee, +5 authors, Benjamin P Berman.
Bioinformatics, 2018 Oct 27; 35(11). PMID: 30364927    Free PMC article.
PretiMeth: precise prediction models for DNA methylation based on single methylation mark.
Jianxiong Tang, Jianxiao Zou, +5 authors, Shicai Fan.
BMC Genomics, 2020 May 18; 21(1). PMID: 32414326    Free PMC article.
Understanding Non-Mendelian Genetic Risk.
Gerhard A Coetzee.
Curr Genomics, 2020 Jun 02; 20(5). PMID: 32476988    Free PMC article.
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Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford progeria syndrome.
Florian Köhler, Felix Bormann, +7 authors, Manuel Rodríguez-Paredes.
Genome Med, 2020 May 27; 12(1). PMID: 32450911    Free PMC article.
Identification of Transcription Factor/Gene Axis in Colon Cancer Using a Methylome Approach.
Jiayu Zhang, Bo Li, +4 authors, Yang Jiang.
Front Genet, 2020 Aug 28; 11. PMID: 32849837    Free PMC article.
Characterization of DNA Methylation Associated Gene Regulatory Networks During Stomach Cancer Progression.
Jun Wu, Yunzhao Gu, +7 authors, Xiaodong Zhao.
Front Genet, 2019 Feb 20; 9. PMID: 30778372    Free PMC article.
TENET 2.0: Identification of key transcriptional regulators and enhancers in lung adenocarcinoma.
Daniel J Mullen, Chunli Yan, +6 authors, Suhn Kyong Rhie.
PLoS Genet, 2020 Sep 15; 16(9). PMID: 32925947    Free PMC article.
Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer.
Aleyna Eray, Perihan Yağmur Güneri, +2 authors, Serap Erkek-Ozhan.
Sci Rep, 2020 Oct 31; 10(1). PMID: 33122695    Free PMC article.
Identification of Prognostic Markers in Cholangiocarcinoma Using Altered DNA Methylation and Gene Expression Profiles.
Nitish Kumar Mishra, Meng Niu, +4 authors, Chittibabu Guda.
Front Genet, 2020 Nov 17; 11. PMID: 33193605    Free PMC article.
DNA methylation during human adipogenesis and the impact of fructose.
Giulia Tini, Vijayalakshmi Varma, +7 authors, Marie-Pier Scott-Boyer.
Genes Nutr, 2020 Nov 28; 15(1). PMID: 33243154    Free PMC article.
The chromatin accessibility landscape of primary human cancers.
M Ryan Corces, Jeffrey M Granja, +22 authors, Howard Y Chang.
Science, 2018 Oct 27; 362(6413). PMID: 30361341    Free PMC article.
Highly Cited.
Mechanisms of DNA Methyltransferase Recruitment in Mammals.
Marthe Laisné, Nikhil Gupta, +2 authors, Pierre-Antoine Defossez.
Genes (Basel), 2018 Dec 14; 9(12). PMID: 30544749    Free PMC article.
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InTAD: chromosome conformation guided analysis of enhancer target genes.
Konstantin Okonechnikov, Serap Erkek, +2 authors, Lukas Chavez.
BMC Bioinformatics, 2019 Feb 02; 20(1). PMID: 30704404    Free PMC article.
Drug Response Associated With and Prognostic lncRNAs Mediated by DNA Methylation and Transcription Factors in Colon Cancer.
Jiayu Zhang, Zhen Shen, +3 authors, Tiancheng Zhao.
Front Genet, 2020 Dec 18; 11. PMID: 33329694    Free PMC article.
Epigenomic Reprogramming toward Mesenchymal-Epithelial Transition in Ovarian-Cancer-Associated Mesenchymal Stem Cells Drives Metastasis.
Huihui Fan, Huda I Atiya, +12 authors, Lan G Coffman.
Cell Rep, 2020 Dec 10; 33(10). PMID: 33296650    Free PMC article.
Endometrial membrane organoids from human embryonic stem cell combined with the 3D Matrigel for endometrium regeneration in asherman syndrome.
Xiuxiu Jiang, Xingmiao Li, +4 authors, Yangyang Li.
Bioact Mater, 2021 May 04; 6(11). PMID: 33937593    Free PMC article.
Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma.
Li Chen, Moli Huang, +21 authors, H Phillip Koeffler.
Gut, 2019 Aug 15; 69(4). PMID: 31409603    Free PMC article.
Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses.
Sheng-Fang Su, Chia-Hsin Liu, +9 authors, Ker-Chau Li.
JCO Precis Oncol, 2021 May 27; 5. PMID: 34036228    Free PMC article.
Integrative molecular characterization of pediatric spinal ependymoma: the UK Children's Cancer and Leukaemia Group study.
Omar Ahmad, Rebecca Chapman, +6 authors, Anbarasu Lourdusamy.
Neurooncol Adv, 2021 May 28; 3(1). PMID: 34041479    Free PMC article.
Integrated Analysis of Whole Genome and Epigenome Data Using Machine Learning Technology: Toward the Establishment of Precision Oncology.
Ken Asada, Syuzo Kaneko, +6 authors, Ryuji Hamamoto.
Front Oncol, 2021 Jun 01; 11. PMID: 34055633    Free PMC article.
Review.