Publications

Interindividual Variability in Imatinib Metabolism in Human Liver Microsomes and Primary Human Hepatocytes: Impact of CYP2C8 and CYP3A Phenotypes

Abstract Imatinib is a kinase inhibitor used in the treatment of chronic myeloid leukemia (CML) and other cancers. Although its pharmacokinetics are generally predictable, substantial interindividual variability in clearance and exposure remains. In this study, we investigated the impact of cytochrome P450 (CYP) enzymes: CYP2C8, CYP3A4, and CYP3A5 phenotypes and genotypes on imatinib metabolism using … Read more

NAT1 and NAT2 Enzyme Activity Drive Interindividual Variability in Sulfamethoxazole N-Acetylation

Abstract Sulfamethoxazole (SMX) is associated with idiosyncratic drug induced liver injury (DILI), which remains difficult to predict. SMX is metabolized by N-acetyltransferases (NAT1/NAT2) to form N4-acetyl sulfamethoxazole (NA-SMX), and by cytochrome P450-mediated oxidation to form SMX-hydroxylamine (SMX-HA). This study aimed to characterize SMX metabolism in vitro and investigate how NAT1 and NAT2 variation influences NA-SMX formation, including the relationship between NAT2 protein levels … Read more

Dynamic activation of rAAV transgene expression by a small molecule that recruits endogenous transcriptional machinery

Abstract Adeno-associated virus (AAV) gene therapies typically use constitutive transgene expression vectors that cannot be altered after vector administration. Here, we describe a bioorthogonal platform for tuning AAV expression which enables the controlled activation of viral transgenes after transduction. This platform uses a small, synthetic DNA-binding protein embedded in the AAV genome coupled with a … Read more

Spt6-Spn1 interaction is required for RNA Polymerase II association and precise nucleosome positioning along transcribed genes

Abstract Spt6-Spn1 is an essential histone chaperone complex that associates with RNA Polymerase II (RNAPII) and reassembles nucleosomes during gene transcription. While the interaction between Spt6 and Spn1 is important for its histone deposition and transcription functions, a precise mechanistic understanding is still limited. Here, using temperature sensitive alleles of spt6 and spn1 that disrupt … Read more

Early life exposure to vitamin D deficiency impairs molecular mechanisms that regulate liver cholesterol biosynthesis, energy metabolism, inflammation, and detoxification

Introduction: Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed.

CHD4 and SMYD1 repress common transcriptional programs in the developing heart

Abstract Regulation of chromatin states is essential for proper temporal and spatial gene expression. Chromatin states are modulated by remodeling complexes composed of components that have enzymatic activities. CHD4 is the catalytic core of the nucleosome remodeling and deacetylase (NuRD) complex, which represses gene transcription. However, it remains to be determined how CHD4, a ubiquitous … Read more

The tardigrade Hypsibius exemplaris dramatically upregulates DNA repair pathway genes in response to ionizing radiation

Summary   Tardigrades can survive remarkable doses of ionizing radiation, up to about 1,000 times the lethal dose for humans. How they do so is incompletely understood. We found that the tardigrade Hypsibius exemplaris suffers DNA damage upon gamma irradiation, but the damage is repaired. We show that this species has a specific and robust … Read more

Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis

Abstract N6-Methyladenosine (m6A) is the most abundant posttranscriptional modification, and its contribution to cancer evolution has recently been appreciated. Renal cancer is the most common adult genitourinary cancer, approximately 85% of which is accounted for by the clear cell renal cell carcinoma (ccRCC) subtype characterized by VHL loss. However, it is unclear whether VHL loss … Read more

Gastrulation-stage alcohol exposure induces similar rates of craniofacial malformations in male and female C57BL/6J mice

Background Prenatal alcohol exposure during gastrulation (embryonic day [E] 7 in mice, ~3rd week of human pregnancy) impairs eye, facial, and cortical development, recapitulating birth defects characteristic of Fetal Alcohol Syndrome (FAS). However, it is not known whether the prevalence or severity of craniofacial features associated with FAS is affected by biological sex. Methods The … Read more

New BARC article: Gestational diabetes mellitus placentas exhibit epimutations at placental development genes

Gestational diabetes mellitus (GDM) is a maternal metabolic disorder that perturbs placental development and increases the risk of offspring short- and long-term metabolic disorders. The mechanisms by which GDM impairs placental development remain poorly understood. Here, we defined the DNA methylome of GDM placentas and determined whether GDM perturbs methylation at genes important for placental … Read more