DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis
Ana Lleo,Weici Zhang,Ming Zhao,Yixin Tan,Francesca Bernuzzi,Bochen Zhu,Qian Liu,Qiqun Tan,Federica Malinverno,Luca Valenti,Tingting Jiang,Lina Tan,Wei Liao,Ross L. Coppel,Pietro Invernizzi,Qianjin Lu,David H. Adams,M. Eric Gershwin +17 more
TLDR
The authors' data provides a set of genes with epigenetic alteration likely to be indicators of autoimmunity and emphasizes the role of CXCR3 in the natural history of PBC.Abstract:
Although the etiology of primary biliary cirrhosis (PBC) remains enigmatic, there are several pieces of data supporting the thesis that a strong genetic predisposition and environmental factors interact to produce a selective loss of tolerance. The striking female predominance of PBC has suggested that this sex predisposition may be secondary to epigenetic alterations on the X chromosome. In the present study, we rigorously defined the X chromosome methylation profile of CD4, CD8, and CD14 cells from 30 PBC patients and 30 controls. Genomic DNA from sorted CD4, CD8, and CD14 subpopulations was isolated, sonicated, and immunoprecipitated for analysis of methylation. All products were hybridized to a custom-tiled four-plex array containing 27,728 CpG islands annotated by UCSC and 22,532 well-characterized RefSeq promoter regions. Furthermore, bisulfite sequencing was then used for validation on a subsequent group of independent samples from PBC patients and controls. Thence, expression levels of selected X-linked genes were evaluated by quantitative real-time PCR with cDNA samples from all subjects. We report herein that a total of 20, 15, and 19 distinct gene promoters reflected a significant difference in DNA methylation in CD4+ T, CD8+ T, and CD14+ cells in patients with PBC. Interestingly, there was hypermethylation of FUNDC2 in CD8+ T cells and a striking demethylation of CXCR3 in CD4+ T cells, which inversely correlated with CXCR3 expression levels in CD4+ T cells from early-stage PBC patients. Our data provides a set of genes with epigenetic alteration likely to be indicators of autoimmunity and emphasizes the role of CXCR3 in the natural history of PBC.read more
Citations
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Journal ArticleDOI
The critical role of epigenetics in systemic lupus erythematosus and autoimmunity.
TL;DR: How genetic studies fail to completely elucidate the pathogenesis of autoimmune diseases is discussed and a comprehensive review on landmark epigenetic findings in autoimmune diseases, taking SLE as an extensively studied example is presented.
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Evolving Trends in Female to Male Incidence and Male Mortality of Primary Biliary Cholangitis
Ana Lleo,Peter Uhd Jepsen,Emanuela Morenghi,Marco Carbone,Luca Moroni,Pier Maria Battezzati,Mauro Podda,Ian R. Mackay,M. Eric Gershwin,Pietro Invernizzi,Pietro Invernizzi +10 more
TL;DR: The authors' data indicate for PBC a sex ratio significantly lower than previously cited, a reversal of the usual latitudinal difference in prevalence and a surprisingly higher overall mortality for male patients.
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The loss of TET2 promotes CD8+ T cell memory differentiation
Shannon A. Carty,Mercy Gohil,Lauren B. Banks,Renee M. Cotton,Matthew E. Johnson,Erietta Stelekati,Andrew D. Wells,Andrew D. Wells,E. John Wherry,Gary A. Koretzky,Gary A. Koretzky,Martha S. Jordan +11 more
TL;DR: It is demonstrated that the methylcytosine dioxygenase ten-eleven translocation (TET)2 regulates CD8+ T cell differentiation and promotes early acquisition of a memory CD8- T cell fate in a cell-intrinsic manner without disrupting Ag-driven cell expansion or effector function.
Journal ArticleDOI
Primary biliary cholangitis
TL;DR: Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid, and conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid.
Journal ArticleDOI
Using GWAS to identify genetic predisposition in hepatic autoimmunity
TL;DR: The rationale for GWAS in general and with specific reference to hepatic autoimmunity is considered and attempts to translate GWAS findings into basic laboratory models including in vivo systems are reviewed and highlighted where clinical observations relate to genetics.
References
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Journal ArticleDOI
Primary biliary cirrhosis.
TL;DR: Mise a jour: anatomopathologie, anomalies immunologiques et pathogenese, tests de laboratoire, manifestations cliniques et troubles associes, evolution, traitement.
Journal ArticleDOI
Primary Biliary Cirrhosis
Keith D. Lindor,M. Eric Gershwin,Raoul Poupon,Marshall M. Kaplan,Nora V. Bergasa,E. Jenny Heathcote +5 more
TL;DR: PBC is a chronic cholestatic liver disease characterized by high-titer serum antimitochondrial autoantibodies (AMAs) and autoimmune-mediated destruction of small and medium-sized intrahepatic bile ducts as discussed by the authors.
Journal Article
Primary Biliary Cirrhosis
TL;DR: Results of abdominal ultrasonography, CT, and MRI were normal, and findings suggested primary biliary cirrhosis (PBC), an autoimmune liver disorder characterized by chronic inflammation as well as fibrous obliteration of the intrahepatic bile ducts.
Journal Article
Short technical reports. Modification of the TRI reagent procedure for isolation of RNA from polysaccharide- and proteoglycan-rich sources.
Piotr Chomczynski,Karol Mackey +1 more
TL;DR: The modified precipitation does not prolong or increase the complexity of the TRI Reagent procedure and was tested by isolation of RNA from polysaccharide- and proteoglycan-rich tissues such as rat liver and aorta.
Journal ArticleDOI
Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus
Biola M. Javierre,Agustín F. Fernández,Julia Richter,Fatima Al-Shahrour,J. Ignacio Martin-Subero,Javier Rodríguez-Ubreva,María Berdasco,Mario F. Fraga,Terrance P. O'Hanlon,Lisa G. Rider,Filipe V. Jacinto,F. Javier López-Longo,Joaquín Dopazo,Marta Forn,Miguel A. Peinado,Luis Carreño,Amr H. Sawalha,John B. Harley,Reiner Siebert,Manel Esteller,Frederick W. Miller,Esteban Ballestar +21 more
TL;DR: The findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.
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