The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Relationship Between Methylome and Transcriptome in Patients With Nonalcoholic Fatty Liver Disease
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Moreover, certain patterns of DNA methylation at fibrosis-related genes, such as those encoding TGFβ1, COL1A1, PDGFα, peroxisome proliferator-activated receptor alpha (PPARα), and peroxisome proliferator-activated receptor delta (PPARδ), can not only distinguish between patients with mild versus advanced MASLD, but also predict future fibrosis progression (169-172).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [169]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Bioconductor: open software development for computational biology and bioinformatics
Gentleman, R. C., Carey, V. J., Bates, D. M., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J., et al. (2004) · Genome biology · doi:10.1186/gb-2004-5-10-r80 · Cited by 12,082
Chalasani, N., Younossi, Z. M., Lavine, J. E., Diehl, A. M., Brunt, E. M., Cusi, K. J., Charlton, M., & Sanyal, A. J. (2012) · Hepatology · doi:10.1002/hep.25762 · Cited by 3,859
Self-citationDNA methylation and human disease
Robertson, K. D. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1655 · Cited by 2,864
The accessible chromatin landscape of the human genome
Thurman, R. E., Rynes, E., Humbert, R., Vierstra, J., Maurano, M. T., Haugen, E., Sheffield, N. C., Stergachis, A. B., Wang, H., Vernot, B., et al. (2012) · Nature · doi:10.1038/nature11232 · Cited by 2,679
Irizarry, R. A., Ladd-Acosta, C., Wen, B., Wu, Z., Montano, C., Onyango, P., Cui, H., Gabo, K., Rongione, M., Webster, M., et al. (2009) · Nature Genetics · doi:10.1038/ng.298 · Cited by 2,177
Transposable elements: targets for early nutritional effects on epigenetic gene regulation
Waterland, R. A., & Jirtle, R. L. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.15.5293-5300.2003 · Cited by 2,019
Doi, A., Park, I., Wen, B., Murakami, P. N., Aryee, M. J., Irizarry, R. A., Herb, B. R., Ladd‐Acosta, C., Rho, J., Loewer, S., et al. (2009) · Nature Genetics · doi:10.1038/ng.471 · Cited by 1,201
The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease
McCullough, A. J. (2004) · Clinics in Liver Disease · doi:10.1016/j.cld.2004.04.004 · Cited by 580
Evaluation of the Infinium Methylation 450K technology
Dedeurwaerder, S., Defrance, M., Calonne, E., Denis, H., Sotiriou, C., & Fuks, F. (2011) · Epigenomics · doi:10.2217/epi.11.105 · Cited by 569
Lu, S. C., Alvarez, L., Huang, Z.-Z., Chen, L., An, W., Corrales, F. J., Avila, M. A., Kanel, G., & Mato, J. M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091016398 · Cited by 449
Liver X receptor in cholesterol metabolism
Zhao, C., & Dahlman‐Wright, K. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0271 · Cited by 425
Moylan, C. A., Pang, H., Dellinger, A. E., Suzuki, A., Garrett, M. E., Guy, C. D., Murphy, S. K., Ashley‐Koch, A. E., Choi, S. S., Michelotti, G. A., et al. (2013) · Hepatology · doi:10.1002/hep.26661 · Cited by 319
Self-citationSavard, C. E., Tartaglione, E. V., Kuver, R., Haigh, G. W., Farrell, G. C., Subramanian, S., Chait, A., Yeh, M. M., Quinn, L. S., & Ioannou, G. N. (2012) · Hepatology · doi:10.1002/hep.25789 · Cited by 297
Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A
Martínez‐Chantar, M. L., Corrales, F. J., Martínez‐Cruz, L. A., García–Trevijano, E. R., Huang, Z., Chen, L., Kanel, G. C., Avila, M. A., Mato, J. M., & Lu, S. C.-L. (2002) · The FASEB Journal · doi:10.1096/fj.02-0078fje · Cited by 278
Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis #
Witek, R. P., Stone, C. W., Karaca, G., Syn, W., Pereira, T. A., Agboola, K. M., Omenetti, A., Jung, Y., Teaberry, V. S., Choi, S. S., et al. (2009) · Hepatology · doi:10.1002/hep.23167 · Cited by 252
Self-citationChanges in methionine adenosyltransferase andS-adenosylmethionine homeostasis in alcoholic rat liver
Lu, S. C.-L., Huang, Z., Yang, H., Mato, J. M., Avila, M. A., & Tsukamoto, H. (2000) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.2000.279.1.g178 · Cited by 195
Self-citationSelçuklu, S. D., Donoghue, M. T. A., Rehmet, K., Gomes, M. D. S., Fort, A., Kovvuru, P., Muniyappa, M. K., Kerin, M. J., Enright, A. J., & Spillane, C. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.335943 · Cited by 185
Cordero, P., Gómez-Uriz, A. M., Campión, J., Milagro, F. I., & Martínez, J. A. (2012) · Genes & Nutrition · doi:10.1007/s12263-012-0300-z · Cited by 183
Hypermethioninemias of genetic and non‐genetic origin: A review
Mudd, S. H. (2011) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.30293 · Cited by 182
Redefining CpG islands using hidden Markov models
Wu, H., Caffo, B. S., Jaffee, H. A., Irizarry, R. A., & Feinberg, A. P. (2010) · Biostatistics · doi:10.1093/biostatistics/kxq005 · Cited by 167
Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis
Dixon, L. J., Berk, M. P., Thapaliya, S., Papouchado, B. G., & Feldstein, A. E. (2012) · Laboratory Investigation · doi:10.1038/labinvest.2012.45 · Cited by 159
Bu, S. Y., & Mashek, D. G. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m009407 · Cited by 138
Nishida, N., Kudo, M., Nagasaka, T., Ikai, I., & Goel, A. (2012) · Hepatology · doi:10.1002/hep.25706 · Cited by 137
Bian, E., Huang, C. Z., Ma, T., Tao, H., Zhang, H., Chang, C. K., Lv, X., & Li, J. (2012) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2012.06.022 · Cited by 126
Antifolate Drugs in Cancer Therapy
(1999) · Humana Press eBooks · doi:10.1007/978-1-59259-725-3 · Cited by 123
Jian, Y. U., Zhang, H. Y., Zhong, Z., Lu, W., Wang, Y., & Jingde, Z. H. U. (2003) · Cell Research · doi:10.1038/sj.cr.7290177 · Cited by 102
Cano, A., Buqué, X., Martinez‐Uña, M., Aurrekoetxea, I., Menor, A., García‐Rodríguez, J. L., Lu, S. C.-L., Martínez‐Chantar, M. L., Mato, J. M., Ochoa, B., et al. (2010) · Hepatology · doi:10.1002/hep.24607 · Cited by 99
Global analysis of DNA methylation in early-stage liver fibrosis
Komatsu, Y., Waku, T., Iwasaki, N., Ono, W., Yamaguchi, C., & Yanagisawa, J. (2012) · BMC Medical Genomics · doi:10.1186/1755-8794-5-5 · Cited by 99
Role of abnormal methionine metabolism in alcoholic liver injury
Lu, S. C.-L., Tsukamoto, H., & Mato, J. M. (2002) · Alcohol · doi:10.1016/s0741-8329(02)00226-4 · Cited by 96
Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancerPreprint
Matsumura, N., Huang, Z., Mori, S., Baba, T., Fujii, S., Konishi, I., Iversen, E. S., Berchuck, A., & Murphy, S. K. (2010) · Genome Research · doi:10.1101/gr.108803.110 · Cited by 95
Self-citationTryndyak, V., Han, T., Muskhelishvili, L., Fuscoe, J. C., Ross, S. A., Beland, F. A., & Pogribny, I. P. (2010) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201000300 · Cited by 89
Frau, M., Tomasi, M. L., Simile, M. M., Demartis, M. I., Salis, F., Latte, G., Calvisi, D. F., Seddaiu, M. A., Daino, L., Feo, C. F., et al. (2012) · Hepatology · doi:10.1002/hep.25643 · Cited by 88
The UCSC cancer genomics browser: update 2011
Sanborn, Z., Benz, S. C., Craft, B., Szeto, C. W., Kober, K. M., Meyer, L. R., Vaske, C. J., Goldman, M. J., Smith, K. E., Kuhn, R. M., et al. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq1113 · Cited by 78
Christensen, K. E., & MacKenzie, R. E. (2008) · Vitamins and hormones · doi:10.1016/s0083-6729(08)00414-7 · Cited by 73
Epigenetic Silencing of ALDH1L1, a Metabolic Regulator of Cellular Proliferation, in Cancers
Oleinik, N. V., Krupenko, N. I., & Krupenko, S. A. (2011) · Genes & Cancer · doi:10.1177/1947601911405841 · Cited by 60
Noninvasive diagnosis of nonalcoholic fatty liver disease
Myers, R. P. (2009) · Annals of Hepatology · doi:10.1016/s1665-2681(19)31823-x · Cited by 59
Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver
Harder, J., Opitz, O. G., Brabender, J., Olschewski, M., Blum, H. E., Nomoto, S., & Usadel, H. (2008) · International Journal of Cancer · doi:10.1002/ijc.23433 · Cited by 58
DNA Methylation Profiles of Organic Anion Transporting Polypeptide 1B3 in Cancer Cell Lines
Ichihara, S., Kikuchi, R., Kusuhara, H., Imai, S., Maeda, K., & Sugiyama, Y. (2010) · Pharmaceutical Research · doi:10.1007/s11095-010-0064-3 · Cited by 44
Analysis of DNA Methylation and Histone Modification Profiles of Liver-Specific Transporters
Imai, S., Kikuchi, R., Kusuhara, H., Yagi, S., Shiota, K., & Sugiyama, Y. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.052589 · Cited by 42
Decreased expression of ALDH1L1 is associated with a poor prognosis in hepatocellular carcinoma
Chen, X.-Q., He, J.-R., & Wang, H. (2011) · Medical Oncology · doi:10.1007/s12032-011-0075-x · Cited by 40
Shimizu, H., Horii, A., Sunamura, M., Motoi, F., Egawa, S., Unno, M., & Fukushige, S. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.06.121 · Cited by 39
Systems Biology for Signaling Networks
Choi, S. (2010) · Systems biology · doi:10.1007/978-1-4419-5797-9 · Cited by 37
Inhibition of human methionine adenosyltransferase 1A transcription by coding region methylation
Tomasi, M. L., Li, T. W. H., Li, M., Mato, J. M., & Lu, S. C.-L. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22875 · Cited by 36
Folate Biochemistry in Relation to Antifolate Selectivity
Kisliuk, R. L. (1999) · Humana Press eBooks · doi:10.1007/978-1-59259-725-3_2 · Cited by 29
A novel four transmembrane spanning protein, CLP24
Kearsey, J., Petit, S., Oliveira, C. D., & Schweighoffer, F. (2004) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.2004.04186.x · Cited by 24
Russmann, S., Junker, E., & Lauterburg, B. H. (2002) · Hepatology · doi:10.1053/jhep.2002.36499 · Cited by 20
Expression of tumor-associated aldehyde dehydrogenase gene in rat hepatoma cell lines.
Lin, K., Brennan, M. D., & Lindahl, R. G. (1988) · PubMed · Cited by 17
Pathogenesis of Obesity-Related Chronic Liver Diseases as the Study Case for the Systems Biology
Baranova, A. V., Birerdinc, A., Estep, M., & Younossi, Z. M. (2010) · Systems biology · doi:10.1007/978-1-4419-5797-9_26 · Cited by 2
Cited by
Sorted by citations
MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease
Eslam, M., Sanyal, A. J., George, J., Sanyal, A., Neuschwander-Tetri, B., Tiribelli, C., Kleiner, D. E., Brunt, E., Bugianesi, E., Yki-Järvinen, H., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.312 · Cited by 3,286
Self-citationBoursier, J., Mueller, O., Barret, M., Machado, M., Fizanne, L., Araujo‐Perez, F., Guy, C. D., Seed, P. C., Rawls, J. F., David, L. A., et al. (2016) · Hepatology · doi:10.1002/hep.28356 · Cited by 1,483
“Several other factors that influence the course of the disease have been identified, such as epigenetics,((4)) hormonal status,((5)) or nutrition.”
BackgroundSelf-citationTriggering and resolution of inflammation in NASH
Schuster, S., Cabrera, D., Arrese, M., & Feldstein, A. E. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0009-6 · Cited by 943
Nonalcoholic fatty liver disease
Brunt, E. M., Wong, V. W., Nobili, V., Day, C. P., Sookoian, S. C., Maher, J. J., Bugianesi, E., Sirlin, C. B., Neuschwander‐Tetri, B. A., & Rinella, M. E. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.80 · Cited by 889
Genetics and epigenetics of NAFLD and NASH: Clinical impact
Eslam, M., Valenti, L., & Romeo, S. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2017.09.003 · Cited by 971
Metadata
- Authors
- Murphy, S. K., Yang, H., Moylan, C. A., Pang, H., Dellinger, A., Abdelmalek, M. F., Garrett, M. E., Ashley–Koch, A., Suzuki, A., Tillmann, H. L., Hauser, M. A., & Diehl, A. M.
- Affiliations
- Duke University (US)
- Corresponding author
- Diehl, Anna Mae
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 145
- Issue
- 5
- Pages
- 1076-1087
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC3805742
- OpenAlex
- W2150020322
- Cited by
- 391
- References
- 48
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 36 · 2023: 37 · 2022: 31 · 2021: 35 · 2020: 31 · 2019: 38 · 2018: 40 · 2017: 32 · 2016: 26 · 2015: 28 · 2014: 17 · 2013: 2
- FWCI
- 10.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Institutes of Health (5rc2aa019399-02)
- National Institute on Alcohol Abuse and Alcoholism (5RC2-AA019399, RC2-AA019399)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007568)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- non-alcoholic fatty liver disease, DNA methylation, transcriptome, liver fibrosis, disease severity, differentially methylated CpG sites, gene expression, FGF2, MAT1A, caspase-1, one-carbon metabolism, NAFLD progression, non-invasive diagnosis
- MeSH terms
- Adult, Biopsy, Diagnosis, Differential, Fatty Liver, Female, Gene Expression Regulation, Humans, Liver, Male, Methionine Adenosyltransferase, Middle Aged, Severity of Illness Index, Cohort Studies, Disease Progression, CpG Islands, DNA Methylation, Caspase 1, Receptor, Fibroblast Growth Factor, Type 2, Transcriptome, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
