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 celltype heterogeneity in the fetal liver.

Pregnane X Receptor and the Gut-Liver Axis: A Recent Update

“…It should be noted that the ontogenic regulation of Cyp3a11 may not be solely PXR dependent, as it has been shown that district chromatin epigenetic signatures, such as increased permissive mark histone H3 lysine 4 di-methylation (H3K4me2) positively associates with the ontogenic increase of Cyp3a11 mRNA in developing mouse liver . During human liver development, the Cyp3a11 ortholog CYP3A4 gene locus is also extensively modified by the histone code, and the postnatal liver has reduced occupancy of repressive histone marks and higher occupancy of active histone marks compared to the fetal liver (Giebel et al, 2016). During aging, Cyp3a11 mRNA displays a consistent male-predominant pattern and decreases earlier in the livers of female mice than age-matched male mice (Fu et al, 2012).…”

Linking the Epigenome with Exposure Effects and Susceptibility: The Epigenetic Seed and Soil Model

“…The age-dependent accumulation of changes in epigenetic modification states correlates with age-related changes in the expression of key metabolic enzymes, such as the cytochrome p450 (CYP) enzyme family (Giebel et al, 2016;Li et al, 2009) and may play a critical role in lifestage-dependent windows of susceptibility (de Magalhães et al, 2009). The diversity and abundance of expressed CYPs changes as a function of age (Hakkola et al, 1998;Parkinson et al, 2004;Stevens et al, 2003) and is an important determinant of inter-individual variability in xenobiotic metabolism (Hughes et al, 1996;Johnson, 2003;Tré luyer et al, 2001).…”

“…Conversely, hepatic CYP3A4 expression is low at birth but increases through childhood and plateaus by adulthood (Stevens et al, 2003). Giebel et al (2016) attributed the ontogeny of CYP3A7 and 3A4 expression to changes in the balance of activating histone H3 lysine 4 trimethylation (H3K4me3) and repressive (H3K27me3) modification levels within the regulatory regions of these genes. The post-natal increase in CYP3A4 expression corresponds to an increase in H3K4me3 abundance, and thus a shift in the balance of H3K4me3/H3K27me3 in favor of gene expression after birth.…”

The Role of CYP3A in Health and Disease

“…For instance, histone modifications may participate in the CYP3A4 and CYP3A7 expression changes that occur in the embryonic period and in the first 2 years after birth. This mechanism seems to be important for CYP3A4, although other mechanisms may play a greater role in the regulation of CYP3A7 during ontogenesis [ 137 ].…”