Epigene'cs, Hygiene Theory & the Origins of Asthma. Molecular Basis for Health & Disease: We are our genes. Health Protein.
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1 Epigene'cs, Hygiene Theory & the Origins of Asthma Andy Liu, MD Pulmonary Section The Breathing Institute Children s Hospital Colorado National Jewish Health University of Colorado Denver School of Medicine Molecular Basis for Health & Disease: We are our genes DNA Replication Transcription Translation Health Protein RNA? Disease p. 1
2 Epigene'c Regula'on of Gene Epression 3 Epigene'c Mechanisms CpG methylation: gene silencing by blocking transcription factor binding histone binding via methyl binding proteins Histone modifications: Methylation, acetylation, phosphorylation, ubiquitination Non-coding microrna s: 22 bp s, bind 3 mrna Block protein translation mrna degradation - Yang I, Schwartz DA. AJRCCM, 109: , p. 2
3 Epigene'cs & Airway Immunology Innate Immune Instruction Antigen + Environmental Signals Dendritic cell Adaptive Immunity Th n STAT4, T-bet RORγT FoP3 Th 1 Th 17 Tr 1 IFN-γ IL-17/22 IL-10 Cell-mediated immunity Auto-immunity/ Inflammation Immune regulation Th 2 IL-4/5/13 Asthma/Atopy Differentiation (Days) Transcription (Hours) What Causes Epigene'c Changes? Endotoin Microbiome Tobacco Smoke Respiratory Virus Air Pollu'on Diet e.g., Folate, famine Medica'ons p. 3
4 DNA Methylation in PBMCs of Inner City African American Children: Inner City Asthma Consortium (NIH/NIAID Schwartz/Busse) 97 atopic asthmatic cases and 97 non-atopic non-asthmatic controls 81 DMRs: 73 hypomethylated, 8 hypermethylated Yang, Pedersen, Liu et al. JACI 2015;136: Methylation-Epression Relationships in PBMCs P< Internally and eternally validated by pyrosequencing Yang, Pedersen, Liu et al. JACI 2015;136: p. 4
5 DNA Methylation in PBMCs of Inner City African American Children 97 atopic asthmatic cases and 97 non-atopic non-asthmatic controls Yang, Pedersen, Liu et al. JACI 2015;136: DNA Methylation in Nasal Epithelial Cells 36 atopic asthmatic cases vs 36 non-atopic non-asthmatic controls 118 DMRs: median difference 6.8% (range %) Yang, Pedersen, Liu et al. JACI 2016; PMID: p. 5
6 Epigenome in Inner City Asthma Epigenome in asthma is different It affects gene transcrip'on Differences are greater in the nose than blood When did it get this way? SMAD3 methyla'on at birth, immune dysregula'on & asthma: Infant Immune Study (ARC/Bio5, Tucson) DeVries A et al. JACI 2017; PMID: p. 6
7 SMAD3 methyla'on at birth, immune dysregula'on & asthma: Infant Immune Study (ARC/Bio5, Tucson) DeVries A et al. JACI 2017; PMID: SMAD3 methyla'on at birth, immune dysregula'on & MATERNAL asthma DeVries A et al. JACI 2017; PMID: p. 7
8 + Animals _ Endotoin _ Allergy Asthma + Young Children _ Protec've Farm Microbiomes - Ege MJ et al. N Engl J Med 2011;364: p. 8
9 Hygiene to Microbiome Hypothesis: current themes From microbial burden/diversity to specific taa to community acovity Include fungi Protectors, pathogens and community keystones Importance of early life Mechanisms Importance of intervenoon - Liu AH. JACI (2015);136: Protec've Mechanisms Segmented filamentous bacteria induce intesonal DC s to induce Th17 development (Ivanov 2009) Bacteroides fragilis produces Polysaccharide A that induces Fop3 T reg development (Mazmanian, Round ) Prenatal Acinetobacter lwoffii epigeneocally opens up IFN- g promoter accessibility & epression (Debarry, Brand ) Schistosome lysophasphaodylserine induce DC s to induce IL- 10- producing T regs (van der Kleij 2002) Less fecal Lachnospira, Veillonella, Faecalibacterium, and Rothia at 3 months, less fecal acetate, & increased asthma risk (CHILD: Arrieta 2015) Less Bifidobacterium, Akkermansia, Faecalibacterium, higher parocular fungi (Candida and Rhodotorula), and a disonct fecal metabolome enriched for pro- inflammatory metabolites induce Th2 CD4+/IL4 cells and reduce FoP3 Tregs via 12,13- DiHOME (WHEALS: Fujimura 2016) p. 9
10 Environment, Suscep'bility & Asthma Endotoin Microbiome Tobacco Smoke Respiratory Virus Air PolluOon Diet Suscep'bility Gene'cs Epigene'cs Asthma Asthma Clinical Research Unit (9W) Andy s Office (AP3) AIRE Lab p. 10
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