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Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease.

Publication ,  Journal Article
Murphy, SK; Yang, H; Moylan, CA; Pang, H; Dellinger, A; Abdelmalek, MF; Garrett, ME; Ashley-Koch, A; Suzuki, A; Tillmann, HL; Hauser, MA; Diehl, AM
Published in: Gastroenterology
November 2013

BACKGROUND & AIMS: Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting noninvasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. METHODS: We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0-1 (mild) and F3-4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. RESULTS: Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P < .05). Methylation at fibroblast growth factor receptor 2, methionine adenosyl methyltransferase 1A, and caspase 1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, and genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and underexpressed. CONCLUSIONS: Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD.

Duke Scholars

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Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

November 2013

Volume

145

Issue

5

Start / End Page

1076 / 1087

Location

United States

Related Subject Headings

  • Transcriptome
  • Severity of Illness Index
  • Receptor, Fibroblast Growth Factor, Type 2
  • Non-alcoholic Fatty Liver Disease
  • Middle Aged
  • Methionine Adenosyltransferase
  • Male
  • Liver
  • Humans
  • Gene Expression Regulation
 

Citation

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Murphy, S. K., Yang, H., Moylan, C. A., Pang, H., Dellinger, A., Abdelmalek, M. F., … Diehl, A. M. (2013). Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology, 145(5), 1076–1087. https://doi.org/10.1053/j.gastro.2013.07.047
Murphy, Susan K., Hyuna Yang, Cynthia A. Moylan, Herbert Pang, Andrew Dellinger, Manal F. Abdelmalek, Melanie E. Garrett, et al. “Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease.Gastroenterology 145, no. 5 (November 2013): 1076–87. https://doi.org/10.1053/j.gastro.2013.07.047.
Murphy SK, Yang H, Moylan CA, Pang H, Dellinger A, Abdelmalek MF, et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology. 2013 Nov;145(5):1076–87.
Murphy, Susan K., et al. “Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease.Gastroenterology, vol. 145, no. 5, Nov. 2013, pp. 1076–87. Pubmed, doi:10.1053/j.gastro.2013.07.047.
Murphy SK, Yang H, Moylan CA, Pang H, Dellinger A, Abdelmalek MF, Garrett ME, Ashley-Koch A, Suzuki A, Tillmann HL, Hauser MA, Diehl AM. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology. 2013 Nov;145(5):1076–1087.
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

November 2013

Volume

145

Issue

5

Start / End Page

1076 / 1087

Location

United States

Related Subject Headings

  • Transcriptome
  • Severity of Illness Index
  • Receptor, Fibroblast Growth Factor, Type 2
  • Non-alcoholic Fatty Liver Disease
  • Middle Aged
  • Methionine Adenosyltransferase
  • Male
  • Liver
  • Humans
  • Gene Expression Regulation