Interactions Between Regulatory Variants in
            <i>CYP7A1</i>
            (Cholesterol 7α-Hydroxylase) Promoter and Enhancer Regions Regulate CYP7A1 Expression

Wang, Daqing; Hartmann, Katherine E.; Seweryn, Michał; Sadée, Wolfgang

doi:10.1161/circgen.118.002082

Cited by 19 publications

(29 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We used our modified protocol [28,29] for 4C template amplification followed by Ion Torrent sequencing. Inverse primers were designed as described [30].…”

Section: Pcr Amplification Of 4c Template and Ion Torrent Sequencingmentioning

confidence: 99%

Cis-acting regulatory elements regulating CYP3A4 transcription in human liver

Collins

Wang

2020

Pharmacogenetics and Genomics

Self Cite

View full text Add to dashboard Cite

The CYP3A4 enzyme is the most abundant drug-metabolizing enzyme in the liver, metabolizing ~50% of commonly used medications. CYP3A4 displays large inter-person variability in expression and enzyme activity with unknown causes. This study aims to identify cis-acting regulatory elements controlling the transcription of CYP3A4, using chromatin conformation capture (4C and 3C assays), chromatin immunoprecipitation followed by qPCR (ChIP-qPCR), CRISPR-mediated deletions of genomic regions and reporter gene assays in primary culture human hepatocytes and hepatic cell lines. 4C assays identified four regions (R1-R4) interacting with the CYP3A4 promoter, one of which overlaps with the previously identified upstream enhancers CLEM4/XREM (R2) while the other three are novel. ChIP-qPCR, reporter gene assays and CRISPR-mediated deletion experiments indicate regulatory roles for both R2 and R4. Interestingly, deletion of R4 increased CYP3A4 while decreasing CYP3A43 expression, possibly due to competitive domain-domain interactions within the CYP3A cluster, supported by deletion of R4 increasing interaction between the CYP3A4 promoter and R2. We also identified a SNP rs62471956 within R4, with the variant allele A having increased transcriptional activity in a reporter gene assay. The rs62471956 A allele is associated with higher CYP3A43 expression and lower CYP3A4 expression in a cohort of 136 liver samples, further supporting the opposing effects of R4 on CYP3A4 and CYP3A43. rs62471956 is in complete LD with CYP3A4*22, potentially contributing to reduced expression of CYP3A4*22. These results validate previously identified enhancers (CLEM4 and XREM) of CYP3A4 and demonstrate additional regulatory mechanisms underlying CYP3A4 transcriptional control via competitive domain-domain interactions within the CYP3A cluster.

show abstract

“…We used our modified protocol [28,29] for 4C template amplification followed by Ion Torrent sequencing. Inverse primers were designed as described [30].…”

Section: Pcr Amplification Of 4c Template and Ion Torrent Sequencingmentioning

confidence: 99%

Cis-acting regulatory elements regulating CYP3A4 transcription in human liver

Collins

Wang

2020

Pharmacogenetics and Genomics

Self Cite

View full text Add to dashboard Cite

show abstract

“…CYP7A1 is critical to cholesterol catabolism and bile acid homeostasis. Thus, upregulated CYP7A1 reduces cholesterol levels [ 121 ]. Therefore, the upregulation of CYP7A1 can decrease cholesterols in plasma via the synthesis of bile acids in chito-oligosaccharide-treated hosts.…”

Section: Alterations Of Gut Microbiota By Chitosan and Its Derivatmentioning

confidence: 99%

Intestinal Population in Host with Metabolic Syndrome during Administration of Chitosan and Its Derivatives

et al. 2020

View full text Add to dashboard Cite

Chitosan and its derivatives can alleviate metabolic syndrome by different regulation mechanisms, phosphorylation of AMPK (AMP-activated kinase) and Akt (also known as protein kinase B), suppression of PPAR-γ (peroxisome proliferator-activated receptor-γ) and SREBP-1c (sterol regulatory element–binding proteins), and translocation of GLUT4 (glucose transporter-4), and also the downregulation of fatty-acid-transport proteins, fatty-acid-binding proteins, fatty acid synthetase (FAS), acetyl-CoA carboxylase (acetyl coenzyme A carboxylase), and HMG-CoA reductase (hydroxy methylglutaryl coenzyme A reductase). The improved microbial profiles in the gastrointestinal tract were positively correlated with the improved glucose and lipid profiles in hosts with metabolic syndrome. Hence, this review will summarize the current literature illustrating positive correlations between the alleviated conditions in metabolic syndrome hosts and the normalized gut microbiota in hosts with metabolic syndrome after treatment with chitosan and its derivatives, implying that the possibility of chitosan and its derivatives to serve as therapeutic application will be consolidated. Chitosan has been shown to modulate cardiometabolic symptoms (e.g., lipid and glycemic levels, blood pressure) as well as gut microbiota. However, the literature that summarizes the relationship between such metabolic modulation of chitosan and prebiotic-like effects is limited. This review will discuss the connection among their structures, biological properties, and prebiotic effects for the treatment of metabolic syndrome. Our hope is that future researchers will consider the prebiotic effects as significant contributors to the mitigation of metabolic syndrome.

show abstract

“…The single-nucleotide polymorphism (SNP) rs9297994 in the 3 UTR of CYP7A1 is also in linkage disequilibrium with rs3808607 in the promoter region. It has been demonstrated that these two SNPs have opposite effects on the mRNA expression of CYP7A1 and determine the risk of IHD and diabetes mellitus [44].…”

Section: Cyp7a1mentioning

confidence: 99%

Genes Potentially Associated with Familial Hypercholesterolemia

et al. 2019

View full text Add to dashboard Cite

This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease involves not only a pathological variant of low-density lipoprotein receptor and its ligands (apolipoprotein B, proprotein convertase subtilisin/kexin type 9 or low-density lipoprotein receptor adaptor protein 1), but also lipids, including sphingolipids, fatty acids, and sterols. The genetic cause of familial hypercholesterolemia is unknown in 20%–40% of the cases. The genes STAP1 (signal transducing adaptor family member 1), CYP7A1 (cytochrome P450 family 7 subfamily A member 1), LIPA (lipase A, lysosomal acid type), ABCG5 (ATP binding cassette subfamily G member 5), ABCG8 (ATP binding cassette subfamily G member 8), and PNPLA5 (patatin like phospholipase domain containing 5), which can cause aberrations of lipid metabolism, are being evaluated as new targets for the diagnosis and personalized management of familial hypercholesterolemia.

show abstract

Interactions Between Regulatory Variants in CYP7A1 (Cholesterol 7α-Hydroxylase) Promoter and Enhancer Regions Regulate CYP7A1 Expression

Cited by 19 publications

References 38 publications

Cis-acting regulatory elements regulating CYP3A4 transcription in human liver

Cis-acting regulatory elements regulating CYP3A4 transcription in human liver

Intestinal Population in Host with Metabolic Syndrome during Administration of Chitosan and Its Derivatives

Genes Potentially Associated with Familial Hypercholesterolemia

Contact Info

Product

Resources

About