Promoter DNA methylation of farnesoid X receptor and pregnane X receptor modulates the intrahepatic cholestasis of pregnancy phenotype.
The intrahepatic cholestasis of pregnancy (ICP) is a multifactorial liver disorder which pathogenesis involves the interplay among abnormal bile acid (BA) levels, sex hormones, environmental factors, and genetic susceptibility. The dynamic nature of ICP that usually resolves soon after delivery suggests the possibility that its pathobiology is under epigenetic modulation. We explored the status of white blood peripheral cells-DNA methylation of CpG-enriched sites at the promoter of targeted genes (FXR/NR1H4, PXR/NR1I2, NR1I3, ESR1, and ABCC2) in a sample of 88 ICP patients and 173 healthy pregnant women in the third trimester of their pregnancies. CpG dinucleotides at the gene promoter of nuclear receptors subfamily 1 members and ABCC2 transporter were highly methylated during healthy pregnancy. We observed significant differences at the distal (-1890) and proximal promoter (-358) CpG sites of the FXR/NR1H4 and at the distal PXR/NR1I2 (-1224) promoter, which were consistently less methylated in ICP cases when compared with controls. In addition, we observed that methylation at FXR/NR1H4-1890 and PXR/NR1I2-1224 promoter sites was highly and positively correlated with BA profiling, particularly, conjugated BAs. Conversely, methylation level at the proximal FXR/NR1H4-358 CpG site was significantly and negatively correlated with the primary cholic and secondary deoxycholic acid. In vitro exploration showed that epiallopregnanolone sulfate, a reported FXR inhibitor, regulates the transcriptional activity of FXR/NR1H4 but seems to be not involved in the methylation changes. In conclusion, the identification of epigenetic marks in target genes provides a basis for the understanding of adverse liver-related pregnancy outcomes, including ICP.
Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
Romina
R
Cabrerizo
Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina ; Research Council in Health, Ciudad Autónoma de Buenos Aires, Argentina.
Gustavo O
GO
Castaño
Department of Molecular Genetics and Biology of the Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
Adriana L
AL
Burgueño
Department of Molecular Genetics and Biology of the Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
Tomas
T
Fernández Gianotti
Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
María Mora
MM
Gonzalez Lopez Ledesma
Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
Diego
D
Flichman
Department of Molecular Genetics and Biology of the Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
Carlos J
CJ
Pirola
Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina ; Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina ; Research Council in Health, Ciudad Autónoma de Buenos Aires, Argentina.
Silvia
S
Sookoian
D000328:Adult; D045744:Cell Line, Tumor; D002780:Cholestasis, Intrahepatic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000090702:Constitutive Androstane Receptor; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D010641:Phenotype; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011280:Pregnanolone / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
D000090702:Constitutive Androstane Receptor; D000089762:Multidrug Resistance-Associated Protein 2; D011280:Pregnanolone; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C000715087:ABCC2 protein, human; C000716327:NR1I3 protein, human; C579439:epiallopregnanolone sulfate