Whole DNA methylome profiling in mice exposed to secondhand smoke

Abstract

Aberration of DNA methylation is a prime epigenetic mechanism of carcinogenesis. Aberrant DNA methylation occurs frequently in lung cancer, with exposure to secondhand smoke (SHS) being an established risk factor. The causal role of SHS in the genesis of lung cancer, however, remains elusive. To investigate whether SHS can cause aberrant DNA methylation in vivo, we have constructed the whole DNA methylome in mice exposed to SHS for a duration of 4 mo, both after the termination of exposure and at ensuing intervals post-exposure (up to 10 mo). Our genome-wide and gene-specific profiling of DNA methylation in the lung of SHS-exposed mice revealed that all groups of SHS-exposed mice and controls share a similar pattern of DNA methylation. Furthermore, the methylation status of major repetitive DNA elements, including long-interspersed nuclear elements (LINE L1), intracisternal A particle long-terminal repeat retrotransposons (IAP-LTR), and short-interspersed nuclear elements (SINE B1), in the lung of all groups of SHS-exposed mice and controls remains comparable. The absence of locus-specific gain of DNA methylation and global loss of DNA methylation in the lung of SHS-exposed mice within a timeframe that precedes neoplastic-lesion formation underscore the challenges of lung cancer biomarker development. Identifying the initiating events that cause aberrant DNA methylation in lung carcinogenesis may help improve future strategies for prevention, early detection and treatment of this highly lethal disease.

Keywords: :

• DNA methylation
• epigenetics
• lung cancer
• nonsmokers
• repetitive DNA elements

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We would like to thank Dr Yong Jiang for technical assistance in the conduct of SHS-exposure experiments, Dr Fong-Fong Chu for help with mouse breeding and colony expansion, and Dr Walter Tsark for helpful discussion on IACUC protocol preparation. Special thanks to the dedicated staff and management of the City of Hope Animal Resources Center, in particular, Armando Amaya, Marie Prez, Lauren Ratcliffe, Yvonne Harper, Donna Isbell, Kenneth Golding, and Dr Richard Ermel. Work of the authors is supported by grants from the American Cancer Society (RSG-11-083-01-CNE) and the University of California Tobacco Related Disease Research Program (18KT-0040 and 20XT-0116) to A.B. None of the authors have conflicts of interest that might be construed to influence the results or interpretation of the data presented in this manuscript. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Supplemental Materials

Supplemental materials may be found here: www.landesbioscience.com/journals/epigenetics/article/22453