TENET 2.0: Identification of key transcriptional regulators and enhancers in lung adenocarcinoma


Autoři: Daniel J. Mullen aff001;  Chunli Yan aff001;  Diane S. Kang aff001;  Beiyun Zhou aff003;  Zea Borok aff001;  Crystal N. Marconett aff001;  Peggy J. Farnham aff001;  Ite A. Offringa aff001;  Suhn Kyong Rhie aff001
Působiště autorů: Department of Biochemistry and Molecular Medicine and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, CA, United States of America aff001;  Department of Surgery, Keck School of Medicine, University of Southern California, CA, United States of America aff002;  Hastings Center for Pulmonary Research and Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, CA, United States of America aff003
Vyšlo v časopise: TENET 2.0: Identification of key transcriptional regulators and enhancers in lung adenocarcinoma. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009023
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009023

Souhrn

Lung cancer is the leading cause of cancer-related death and lung adenocarcinoma is its most common subtype. Although genetic alterations have been identified as drivers in subsets of lung adenocarcinoma, they do not fully explain tumor development. Epigenetic alterations have been implicated in the pathogenesis of tumors. To identify epigenetic alterations driving lung adenocarcinoma, we used an improved version of the Tracing Enhancer Networks using Epigenetic Traits method (TENET 2.0) in primary normal lung and lung adenocarcinoma cells. We found over 32,000 enhancers that appear differentially activated between normal lung and lung adenocarcinoma. Among the identified transcriptional regulators inactivated in lung adenocarcinoma vs. normal lung, NKX2-1 was linked to a large number of silenced enhancers. Among the activated transcriptional regulators identified, CENPA, FOXM1, and MYBL2 were linked to numerous cancer-specific enhancers. High expression of CENPA, FOXM1, and MYBL2 is particularly observed in a subgroup of lung adenocarcinomas and is associated with poor patient survival. Notably, CENPA, FOXM1, and MYBL2 are also key regulators of cancer-specific enhancers in breast adenocarcinoma of the basal subtype, but they are associated with distinct sets of activated enhancers. We identified individual lung adenocarcinoma enhancers linked to CENPA, FOXM1, or MYBL2 that were associated with poor patient survival. Knockdown experiments of FOXM1 and MYBL2 suggest that these factors regulate genes involved in controlling cell cycle progression and cell division. For example, we found that expression of TK1, a potential target gene of a MYBL2-linked enhancer, is associated with poor patient survival. Identification and characterization of key transcriptional regulators and associated enhancers in lung adenocarcinoma provides important insights into the deregulation of lung adenocarcinoma epigenomes, highlighting novel potential targets for clinical intervention.

Klíčová slova:

Adenocarcinoma of the lung – Breast cancer – DNA methylation – Gene expression – Lung and intrathoracic tumors – Regulator genes – Secondary lung tumors – Transcriptional control


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