Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers

Charles E. Mordaunt, Dorothy A. Kieffer, Noreene M. Shibata, Anna Członkowska, Tomasz Litwin, Karl Heinz Weiss, Yihui Zhu, Christopher Bowlus, Souvik Sarkar, Stewart Cooper, Yu-Jui Yvonne Wan, Mohamed R Ali, Janine M LaSalle, Valentina Medici

Research output: Contribution to journalArticle

Abstract

Background: Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes. Results: WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9. Conclusions: We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.

Original languageEnglish (US)
Article number0255
JournalEpigenetics and Chromatin
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2019

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Hepatolenticular Degeneration
Hematologic Diseases
Epigenomics
Liver
Genome
Phenotype
DNA Methylation
Polycomb Repressive Complex 1
Copper
Hepatocyte Nuclear Factor 4
Retinoid X Receptor alpha
Cell Physiological Phenomena
Genetic Association Studies

Keywords

  • Biomarker
  • Blood
  • Chromatin
  • Copper
  • DNA methylation
  • Enhancer
  • Epigenetics
  • Liver
  • Whole-genome bisulfite sequencing
  • Wilson disease

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers. / Mordaunt, Charles E.; Kieffer, Dorothy A.; Shibata, Noreene M.; Członkowska, Anna; Litwin, Tomasz; Weiss, Karl Heinz; Zhu, Yihui; Bowlus, Christopher; Sarkar, Souvik; Cooper, Stewart; Wan, Yu-Jui Yvonne; Ali, Mohamed R; LaSalle, Janine M; Medici, Valentina.

In: Epigenetics and Chromatin, Vol. 12, No. 1, 0255, 01.01.2019.

Research output: Contribution to journalArticle

Mordaunt, Charles E. ; Kieffer, Dorothy A. ; Shibata, Noreene M. ; Członkowska, Anna ; Litwin, Tomasz ; Weiss, Karl Heinz ; Zhu, Yihui ; Bowlus, Christopher ; Sarkar, Souvik ; Cooper, Stewart ; Wan, Yu-Jui Yvonne ; Ali, Mohamed R ; LaSalle, Janine M ; Medici, Valentina. / Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers. In: Epigenetics and Chromatin. 2019 ; Vol. 12, No. 1.
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title = "Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers",
abstract = "Background: Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes. Results: WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9. Conclusions: We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.",
keywords = "Biomarker, Blood, Chromatin, Copper, DNA methylation, Enhancer, Epigenetics, Liver, Whole-genome bisulfite sequencing, Wilson disease",
author = "Mordaunt, {Charles E.} and Kieffer, {Dorothy A.} and Shibata, {Noreene M.} and Anna Członkowska and Tomasz Litwin and Weiss, {Karl Heinz} and Yihui Zhu and Christopher Bowlus and Souvik Sarkar and Stewart Cooper and Wan, {Yu-Jui Yvonne} and Ali, {Mohamed R} and LaSalle, {Janine M} and Valentina Medici",
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T1 - Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers

AU - Mordaunt, Charles E.

AU - Kieffer, Dorothy A.

AU - Shibata, Noreene M.

AU - Członkowska, Anna

AU - Litwin, Tomasz

AU - Weiss, Karl Heinz

AU - Zhu, Yihui

AU - Bowlus, Christopher

AU - Sarkar, Souvik

AU - Cooper, Stewart

AU - Wan, Yu-Jui Yvonne

AU - Ali, Mohamed R

AU - LaSalle, Janine M

AU - Medici, Valentina

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes. Results: WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9. Conclusions: We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.

AB - Background: Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes. Results: WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9. Conclusions: We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.

KW - Biomarker

KW - Blood

KW - Chromatin

KW - Copper

KW - DNA methylation

KW - Enhancer

KW - Epigenetics

KW - Liver

KW - Whole-genome bisulfite sequencing

KW - Wilson disease

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U2 - 10.1186/s13072-019-0255-z

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M3 - Article

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