Genetic and epigenetic influence on the response to environmental particulate matter  Hong Ji, PhD, Gurjit K. Khurana Hershey, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 129, Issue 1, Pages 33-41 (January 2012) DOI: 10.1016/j.jaci.2011.11.008 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Epigenetic mechanisms regulate gene function and are affected by PM exposure. DNA methylation, posttranslational histone modification, histone variation, chromatin remodeling complexes, noncoding RNA, and other unidentified epigenetic factors interact with each other to delicately regulate gene function. PM exposure can potentially affect all these epigenetic modifications and result in altered gene expression. PM exposure induces changes in DNA methylation, histone acetylation, and miRNA expression that correlate with gene expression differences. Black circles represent PM. CHD, Chromodomain helicase DNA binding proteins; H2AX, H2A histone family, member X; H2AZ, H2A histone family, member Z; INO80, DNA helicase INO80; ISWI, ISWI ATPase; SWI/SNF, SWItch/Sucrose nonfermentable proteins. Journal of Allergy and Clinical Immunology 2012 129, 33-41DOI: (10.1016/j.jaci.2011.11.008) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Potential mechanism by which PM affects the epigenome. Oxidative stress generated by PM might interfere with the methylation cycle by depleting glutathione, thus promoting epigenetic changes. Levels of S-adenosylmethionine (SAM), the methyl donor, are maintained by the methylation cycle. After SAM donates its methyl group, it is converted into homocysteine, which recycles back to SAM (SAM → homocysteine → methionine → SAM). This recycling is catalyzed by methionine synthase (MS), which requires an active form of B12 (methylcobalamin) and folate (5-methyl-THF). PM induces oxidation of glutathione (GSH) to glutathione disulfide (GSSG) and decreases the levels of homocysteine in the methylation cycle. Thus cellular levels of methionine and SAM decrease, resulting in reduced methylation of DNA, RNA, protein, and lipids. Journal of Allergy and Clinical Immunology 2012 129, 33-41DOI: (10.1016/j.jaci.2011.11.008) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions