Histone Modifications Regulate the Developmental Expression of Human Hepatic UDP-Glucuronosyltransferase 1A1

Abstract

Human UDP-glucuronosyltransferase 1A1 (UGT1A1) is a unique enzyme involved in bilirubin conjugation. We previously characterized the hepatic expression of transcription factors affecting UGT1A1 expression during development. Accordingly, in this study, we characterized the ontogenetic expression of hepatic UGT1A1 from the perspective of epigenetic regulation. We observed significant histone-3-lysine-4 dimethylation (H3K4me2) enrichment in the adult liver and histone-3-lysine-27 trimethylation (H3K27me3) enrichment in the fetal liver, indicating that dynamic alterations of histone methylation were associated with ontogenetic UGT1A1 expression. We further showed that the transcription factor hepatocyte nuclear factor 1 (HNF1A) affects histone modifications around the locus. In particular, we demonstrated that by recruiting HNF1A the cofactors mixed-lineage leukemia 1, the transcriptional coactivator p300, and nuclear receptor coactivator 6 aggregate at the promoter, thereby regulating histone modifications and subsequent UGT1A1 expression. In this study, we proposed new ideas for the developmental regulation of metabolic enzymes via histone modifications, and our findings will potentially contribute to the development of age-specific therapies.

Regulation of Hepatic UGT2B15 by Methylation in Adults of Asian Descent

“…Moreover, a strong Asian linkage is not surprising, as PI are theorized to have originated in Asia and mixed extensively with Melanesians both depositing and accumulating genes into their genomes during colonization of the Pacific Islands [ 33 ], which has been further corroborated by both Y chromosome and mitochondrial DNA analyses [ 34 ]. Finally, our work is complemented by recent data demonstrating that hepatic UGT1A1 can be regulated during early human development by histone modification [ 35 ], a novel and interesting finding that supports the concept that UGTs can be regulated at the transcriptional level through genetic mechanisms. Having said this, we believe that future work in this area will need to encompass protein-level studies with Western blot of UGT2B15 and/or activity studies to confirm if these results found at the mRNA levels also follow through to the levels of enzyme proteins and their function.…”

Epigenetics and microRNAs in UGT1As

“…They found that high expression of UGT1A1 in the adult liver was related to enrichment of the transcriptional activation marker H3K4me2. The inhibition of fetal UGT1A1 expression was consistent with the high enrichment of enhancer of zest homolog 2 (EZH2) of the UGT1A1 promoter and the transcriptional suppression marker H3K4me3 (catalyzed by EZH2) [ 58 ]. Children with hyperbilirubinemia are more likely to develop infection during clinical treatment.…”

“…Histone modifications are regulated while regulating gene expression. Knockout of the TF HNF1α has been confirmed to reduce the enrichment of H3K4me2 in the promoter region of UGT1A1 [ 58 ]. Oxidative stress can regulate histone-related enzymes to upregulate the level of H3K4me2 [ 68 ].…”

Prenatal Lipopolysaccharide Exposure Alters Hepatic Drug-Metabolizing Enzyme Expression in Mouse Offspring via Histone Modifications

“…Chromatin Immunoprecipitation (ChIP) analysis was performed using frozen liver samples, as described previously [ 20 , 28 , 29 ], with minor modifications. Briefly, approximately 100 mg liver samples were crosslinked with 1% formaldehyde for 10 min and halted by 125 mM glycine.…”