Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny

Non-standard abbreviations: bp(s), base pair(s); C/EBP, CCAAT/enhancer binding protein; ChIP, chromatin immunoprecipitation; CLEM4, constitutive liver enhancer module 4; Cq, quantification cycle; DME, drug metabolizing enzyme; HNF4α, hepatocyte nuclear factor 4 alpha; PXR, pregnane X receptor; qPCR, quantitative polymerase chain reaction; TBP, TATAbox binding protein; TFIID, transcription factor II D; TSS, transcription start site; USF1, upstream stimulatory factor 1; XREM, xenobiotic-response enhancer module DMD #69344 3 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 occupancy by modified histones observed is consistent with chromatin structural dynamics contributing to CYP3A4 ontogeny, although the data is less conclusive regarding CYP3A7. Interpretation of the latter data may be confounded by cell-type heterogeneity in the fetal liver. DMD #69344

Special Section on Pediatric Drug Disposition and Pharmacokinetics Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny s

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 celltype heterogeneity in the fetal liver

Polymer graph neural networks for multitask property learning

Abstract The prediction of a variety of polymer properties from their monomer composition has been a challenge for material informatics, and their development can lead to a more effective exploration of the material space. In this work, PolymerGNN, a multitask machine learning architecture that relies on polymeric features and graph neural networks has been developed towards this goal. PolymerGNN provides accurate estimates for polymer properties based on a database of complex and heterogeneous polyesters (linear/branched, homopolymers/copolymers) with experimentally refined properties. In PolymerGNN, each polyester is represented as a set of monomer units, which are introduced as molecular graphs. A virtual screening of a large, computationally generated database with materials of variable composition was performed, a task that demonstrates the applicability of the PolymerGNN on future studies that target the exploration of the polymer space. Finally, a discussion on the explainability of the models is provided

Case Report Venous Air Embolism Leading to Cardiac Arrest in an Infant with Cyanotic Congenital Heart Disease

Gas emboli, including venous and arterial, are a rare but important complication of pediatric cardiac surgery. They have the potential to have devastating consequences and require prompt recognition and treatment. We present a case of gas embolism occurring in the immediate postoperative period in an infant with cyanotic congenital heart disease after palliative cardiac surgery resulting in cardiopulmonary arrest. The embolism was diagnosed by visualization of air within the vessel creating an airlock and occluding pulmonary blood flow

Data from: Developmental expression of drug metabolizing enzymes: impact on disposition in neonates and young children

Profound changes in drug metabolizing enzyme expression occurs during development that impacts drug efficacy and the risk of adverse events in the neonate and young child. A review of our current knowledge suggests individual hepatic drug metabolizing enzymes can be categorized into one of three classes based on developmental trajectories. The time frame for the perinatal changes observed for both Class 1 and Class 3 enzymes varies considerably between different enzymes. However, for a given enzyme, significant interindividual variation is observed in the timing of the perinatal changes, creating windows of hypervariability. Genetic variation clearly impacts drug disposition in children. However, developmental factors can dominate pharmacogenetic factors. Thus, a major challenge in applying pharmacogenomics to improve pediatric drug safety is determining at what age functional genetic variants identified in adults become a major determinant of expression in children. Developmental and genetic data on drug metabolizing enzyme ontogeny, as well as age-dependent changes in other physiological factors impacting drug disposition, can be integrated into physiologically-based pharmacokinetic models. Such models have proven useful in predicting the range of expected metabolic capacities at a given age