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 Coppel, Pietro Invernizzi, Qianjin Lu, David H. Adams, M. Eric Gershwin

Research output: Contribution to journalArticle

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Abstract

Background: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article number61
JournalClinical Epigenetics
Volume7
Issue number1
DOIs
StatePublished - Jul 7 2015

Fingerprint

DNA Fingerprinting
Biliary Liver Cirrhosis
X Chromosome
DNA Methylation
T-Lymphocytes
Epigenomics
Methylation
X-Linked Genes
CpG Islands
Genetic Predisposition to Disease
Autoimmunity
Genetic Promoter Regions
Genes
Real-Time Polymerase Chain Reaction
Complementary DNA
DNA

Keywords

  • CXCR3
  • Primary biliary cirrhosis
  • X chromosome

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Developmental Biology
  • Genetics(clinical)

Cite this

DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis. / Lleo, Ana; Zhang, Weici; Zhao, Ming; Tan, Yixin; Bernuzzi, Francesca; Zhu, Bochen; Liu, Qian; Tan, Qiqun; Malinverno, Federica; Valenti, Luca; Jiang, Tingting; Tan, Lina; Liao, Wei; Coppel, Ross; Invernizzi, Pietro; Lu, Qianjin; Adams, David H.; Gershwin, M. Eric.

In: Clinical Epigenetics, Vol. 7, No. 1, 61, 07.07.2015.

Research output: Contribution to journalArticle

Lleo, A, Zhang, W, Zhao, M, Tan, Y, Bernuzzi, F, Zhu, B, Liu, Q, Tan, Q, Malinverno, F, Valenti, L, Jiang, T, Tan, L, Liao, W, Coppel, R, Invernizzi, P, Lu, Q, Adams, DH & Gershwin, ME 2015, 'DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis', Clinical Epigenetics, vol. 7, no. 1, 61. https://doi.org/10.1186/s13148-015-0098-9
Lleo, Ana ; Zhang, Weici ; Zhao, Ming ; Tan, Yixin ; Bernuzzi, Francesca ; Zhu, Bochen ; Liu, Qian ; Tan, Qiqun ; Malinverno, Federica ; Valenti, Luca ; Jiang, Tingting ; Tan, Lina ; Liao, Wei ; Coppel, Ross ; Invernizzi, Pietro ; Lu, Qianjin ; Adams, David H. ; Gershwin, M. Eric. / DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis. In: Clinical Epigenetics. 2015 ; Vol. 7, No. 1.
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abstract = "Background: 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. Results: 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. Conclusions: 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.",
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AU - Lleo, Ana

AU - Zhang, Weici

AU - Zhao, Ming

AU - Tan, Yixin

AU - Bernuzzi, Francesca

AU - Zhu, Bochen

AU - Liu, Qian

AU - Tan, Qiqun

AU - Malinverno, Federica

AU - Valenti, Luca

AU - Jiang, Tingting

AU - Tan, Lina

AU - Liao, Wei

AU - Coppel, Ross

AU - Invernizzi, Pietro

AU - Lu, Qianjin

AU - Adams, David H.

AU - Gershwin, M. Eric

PY - 2015/7/7

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N2 - Background: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Results: 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. Conclusions: 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.

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