Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits.
Although technological advances now allow increased tumor profiling, a detailed understanding of the mechanisms leading to the development of different cancers remains elusive. Our approach toward understanding the molecular events that lead to cancer is to characterize changes in transcriptional regulatory networks between normal and tumor tissue. Because enhancer activity is thought to be critical in regulating cell fate decisions, we have focused our studies on distal regulatory elements and transcription factors that bind to these elements.



Using DNA methylation data, we identified more than 25,000 enhancers that are differentially activated in breast, prostate, and kidney tumor tissues, as compared to normal tissues. We then developed an analytical approach called Tracing Enhancer Networks using Epigenetic Traits that correlates DNA methylation levels at enhancers with gene expression to identify more than 800,000 genome-wide links from enhancers to genes and from genes to enhancers. We found more than 1200 transcription factors to be involved in these tumor-specific enhancer networks. We further characterized several transcription factors linked to a large number of enhancers in each tumor type, including GATA3 in non-basal breast tumors, HOXC6 and DLX1 in prostate tumors, and ZNF395 in kidney tumors. We showed that HOXC6 and DLX1 are associated with different clusters of prostate tumor-specific enhancers and confer distinct transcriptomic changes upon knockdown in C42B prostate cancer cells. We also discovered de novo motifs enriched in enhancers linked to ZNF395 in kidney tumors.



Our studies characterized tumor-specific enhancers and revealed key transcription factors involved in enhancer networks for specific tumor types and subgroups. Our findings, which include a large set of identified enhancers and transcription factors linked to those enhancers in breast, prostate, and kidney cancers, will facilitate understanding of enhancer networks and mechanisms leading to the development of these cancers.
Department of Biochemistry and Molecular Medicine and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1450 Biggy Street, NRT G511B, Los Angeles, CA 90089-9601 USA.
Suhn Kyong
SK
Rhie
Department of Biochemistry and Molecular Medicine and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1450 Biggy Street, NRT G511B, Los Angeles, CA 90089-9601 USA.
Yu
Y
Guo
Department of Biochemistry and Molecular Medicine and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1450 Biggy Street, NRT G511B, Los Angeles, CA 90089-9601 USA.
Yu Gyoung
YG
Tak
Department of Biochemistry and Molecular Medicine and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1450 Biggy Street, NRT G511B, Los Angeles, CA 90089-9601 USA.
Lijing
L
Yao
Van Andel Research Institute, Grand Rapids, MI 49503 USA.
Hui
H
Shen
Van Andel Research Institute, Grand Rapids, MI 49503 USA.
Gerhard A
GA
Coetzee
Van Andel Research Institute, Grand Rapids, MI 49503 USA.
Peter W
PW
Laird
Department of Biochemistry and Molecular Medicine and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1450 Biggy Street, NRT G511B, Los Angeles, CA 90089-9601 USA.
Peggy J
PJ
Farnham
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C088334:Distal-less homeobox proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C094289:HOXC6 protein, human; D006657:Histones; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C484332:ZNF395 protein, human
DNA methylation; Enhancer; Epigenetics; Networks; Transcription factor