title: Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny.
abstract: Variability in drug-metabolizing enzyme developmental trajectories contributes to interindividual differences in susceptibility to chemical toxicity and adverse drug reactions, particularly in the first years of life. Factors linked to these interindividual differences are largely unknown, but molecular mechanisms regulating ontogeny are likely involved. To evaluate chromatin structure dynamics as a likely contributing mechanism, age-dependent changes in modified and variant histone occupancy were evaluated within known CYP3A4 and 3A7 regulatory domains. Chromatin immunoprecipitation using fetal or postnatal human hepatocyte chromatin pools followed by quantitative polymerase chain reaction DNA amplification was used to determine relative chromatin occupancy by modified and variant histones. Chromatin structure representing a poised transcriptional state (bivalent chromatin), indicated by the occupancy by modified histones associated with both active and repressed transcription, was observed for CYP3A4 and most 3A7 regulatory regions in both postnatal and fetal livers. However, the CYP3A4 regulatory regions had significantly greater occupancy by modified histones associated with repressed transcription in the fetal liver. Conversely, some modified histones associated with active transcription exhibited greater occupancy in the postnatal liver. CYP3A7 regulatory regions also had significantly greater occupancy by modified histones associated with repressed transcription in the fetus. The observed occupancy by modified histones is consistent with chromatin structural dynamics contributing to CYP3A4 ontogeny, although the data are less conclusive regarding CYP3A7. Interpretation of the latter data may be confounded by cell-type heterogeneity in the fetal liver.
authors.affiliation: Departments of Pediatrics and Pharmacology and Toxicology, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin (N.L.G., J.D.S., D.G.M., K.Y., P.M.S., R.N.H.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (K.D., R.G., S.C.S.).
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Giebel
authors.affiliation: Departments of Pediatrics and Pharmacology and Toxicology, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin (N.L.G., J.D.S., D.G.M., K.Y., P.M.S., R.N.H.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (K.D., R.G., S.C.S.).
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Shadley
authors.affiliation: Departments of Pediatrics and Pharmacology and Toxicology, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin (N.L.G., J.D.S., D.G.M., K.Y., P.M.S., R.N.H.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (K.D., R.G., S.C.S.).
authors.forename: D Gail
authors.initials: DG
authors.lastname: McCarver
authors.affiliation: Departments of Pediatrics and Pharmacology and Toxicology, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin (N.L.G., J.D.S., D.G.M., K.Y., P.M.S., R.N.H.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (K.D., R.G., S.C.S.).
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dorko
authors.affiliation: Departments of Pediatrics and Pharmacology and Toxicology, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin (N.L.G., J.D.S., D.G.M., K.Y., P.M.S., R.N.H.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (K.D., R.G., S.C.S.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Gramignoli
authors.affiliation: Departments of Pediatrics and Pharmacology and Toxicology, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin (N.L.G., J.D.S., D.G.M., K.Y., P.M.S., R.N.H.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (K.D., R.G., S.C.S.).
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Strom
authors.affiliation: Departments of Pediatrics and Pharmacology and Toxicology, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin (N.L.G., J.D.S., D.G.M., K.Y., P.M.S., R.N.H.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (K.D., R.G., S.C.S.).
authors.forename: Ke
authors.initials: K
authors.lastname: Yan
authors.affiliation: Departments of Pediatrics and Pharmacology and Toxicology, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin (N.L.G., J.D.S., D.G.M., K.Y., P.M.S., R.N.H.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (K.D., R.G., S.C.S.).
authors.forename: Pippa M
authors.initials: PM
authors.lastname: Simpson
authors.affiliation: Departments of Pediatrics and Pharmacology and Toxicology, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin (N.L.G., J.D.S., D.G.M., K.Y., P.M.S., R.N.H.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (K.D., R.G., S.C.S.) hines.ronald@epa.gov.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Hines
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D022781:Hepatocytes / Q000201:enzymology; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008099:Liver / Q000196:embryology / Q000201:enzymology*; D008875:Middle Aged; D009690:Nucleic Acid Conformation; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human