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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.
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“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]
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Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)
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Evaluating causality of cellular senescence in non-alcoholic fatty liver disease
Meijnikman, A. S., Herrema, H., Scheithauer, T. P. M., Kroon, J., Nieuwdorp, M., & Groen, A. K. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100301 · Cited by 81
“distinguished from individualswithNAFLDwith advancedfibrosis based on different methylation patterns.(128) Individuals with advanced fibrosis had more hypomethylated genes in their liver”
BackgroundSzukiewicz, D., Trojanowski, S., Kociszewska, A., & Szewczyk, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314663 · Cited by 81
The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease
Werge, M. P., McCann, A., Galsgaard, E. D., Holst, D., Bugge, A. K., Albrechtsen, N. J. W., & Gluud, L. L. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10051081 · Cited by 78
Zubiete‐Franco, I., García‐Rodríguez, J. L., Martinez‐Uña, M., Martínez-López, N., Woodhoo, A., de Juan, V. G., Beraza, N., Lage, S., Andrade, F., Llarena, M., et al. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.08.037 · Cited by 75
“Recently, it was shown that GNMT mRNA levels were often repressed in advanced NAFLD patients[12].”
BackgroundInfluentialTaghdouini, A. E., Sørensen, A. L., Reiner, A. H., Coll, M., Verhulst, S., Mannaerts, I., Øie, C. I., Smedsrød, B. H., Najimi, M., Sokal, E. M., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4925 · Cited by 72
Nishida, N., Yada, N., Hagiwara, S., Sakurai, T., Kitano, M., & Kudo, M. (2016) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.13318 · Cited by 72
Epigenetic Mechanisms in Hepatic Stellate Cell Activation During Liver Fibrosis and Carcinogenesis
Bárcena‐Varela, M., Colyn, L., & Fernández‐Barrena, M. G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102507 · Cited by 74
“They found that DNA methylation status at specific CpGs might be useful for predicting progression of the disease and development of fibrosis, further supporting their previous studies on DNA methylome signatures and NAFLD patient’s stratification [83].”
ResultGenetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics
Sookoian, S. C., & Pirola, C. J. (2019) · Seminars in Liver Disease · doi:10.1055/s-0039-1679920 · Cited by 78
Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action
de Mello, V. D., Matte, A., Perfilyev, A., Männistö, V., Rönn, T., Nilsson, E., Käkelä, P., Ling, C., & Pihlajamäki, J. (2017) · Epigenetics · doi:10.1080/15592294.2017.1294305 · Cited by 73
“We further tested if epigenetic changes in the liver were associated with clinical phenotypes that are related to NAFLD.”
BackgroundResultInfluentialFujiwara, N., Kobayashi, M., Fobar, A. J., Hoshida, A., Marquez, C. A., Koneru, B., Panda, G., Taguri, M., Qian, T., Raman, I., et al. (2021) · Med · doi:10.1016/j.medj.2021.03.017 · Cited by 70
Nonalcoholic steatohepatitis is associated with a state of betaine‐insufficiency
Sookoian, S., Puri, P., Castaño, G. O., Scian, R., Mirshahi, F., Sanyal, A. J., & Pirola, C. J. (2016) · Liver International · doi:10.1111/liv.13249 · Cited by 68
Genetic and epigenetic mechanisms of NASH
Eslam, M., & George, J. (2015) · Hepatology International · doi:10.1007/s12072-015-9689-y · Cited by 67
“[84] Genome-wide methylation profiles Mild disease (F0–F1) versus advanced NAFLD (F3–F4) 56 NAFLD patients in the discovery cohort and 34 in the replication cohort”
BackgroundWnt signaling in liver regeneration, disease, and cancer
Zou, G., & Park, J.-I. (2023) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2022.0058 · Cited by 64
Jia, X., & Zhai, T. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00599 · Cited by 63
“Identifying gene-specific expression patterns has been useful in the understanding of pathogenic mechanisms or therapeutic assessment for multiple diseases, NAFLD included (6, 7).”
Backgroundp53 as a Dichotomous Regulator of Liver Disease: The Dose Makes the Medicine
Krstić, J., Galhuber, M., Schulz, T. J., Schupp, M., & Prokesch, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030921 · Cited by 65
“Besides genetic [6] and epigenetic (mostly differential DNA methylation [7]) aberrations, infection with hepatitis B and C virus and aflatoxin B1 exposure were historically prevalent risk factors for liver disease development.”
BackgroundLiang, N., Damdimopoulos, A., Goñi, S., Huang, Z.-Q., Vedin, L.-L., Jakobsson, T., Giudici, M., Ahmed, O., Pedrelli, M., Barilla, S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09524-z · Cited by 56
Methionine adenosyltransferases in liver health and diseases
Ramani, K., & Lu, S. C.-L. (2017) · Liver Research · doi:10.1016/j.livres.2017.07.002 · Cited by 65
Mitochondrial role in the neonatal predisposition to developing nonalcoholic fatty liver disease
Baker, P. R., & Friedman, J. E. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120846 · Cited by 64
Lai, Z., Chen, J., Ding, C., Wong, K., Chen, X., Pu, L., Huang, Q., Chen, X., Cheng, Z., Liu, Y., et al. (2019) · Obesity · doi:10.1002/oby.22667 · Cited by 61
“For example, the DNA methylation levels of antifibrogenic genes (peroxisome proliferator activated receptor [PPAR] α, γ, and δ) in the liver were found to increase with hepatic fibrosis severity in patients with NAFLD and alcoholic fatty liver disease (4-6).”
BackgroundNAFLD-Associated HCC: Progress and Opportunities
Geh, D., Anstee, Q. M., & Reeves, H. L. (2021) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s272213 · Cited by 64
“74,75 Importantly the methylation of circulating cell-free DNA (cfDNA) can be analysed.”
Jurado‐Ruiz, E., Varela, L. M., Luque‐Sierra, A., Berná, G., Cahuana, G. M., Martínez‐Force, E., Gallego‐Durán, R., Soria, B., de Roos, B., Romero‐Gómez, M., et al. (2016) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201600549 · Cited by 60
“Additionally, livers with advanced NAFLD show increased expression of hypomethylated genes relative to that in livers with mild NAFLD [35], and hypomethylation is very important for the progression of liver fibrosis in the early stages of the disease [36].”
BackgroundHotta, K., Kitamoto, A., Kitamoto, T., Ogawa, Y., Honda, Y., Kessoku, T., Yoneda, M., Imajo, K., Tomeno, W., Saito, S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-31886-5 · Cited by 59
Epigenetics of Hepatic Insulin Resistance
Maude, H., Sanchez-Cabanillas, C., & Cebola, I. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.681356 · Cited by 64
“In it perhaps not entirely unexpected that the methylation of FGFR2 was found markedly altered in advanced NAFLD, with 23 CpG sites hypomethylated, promoting its overexpression and the establishment of an inflammatory and pro-fibrotic niche (75).”
BackgroundEpigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation
Wang, S., Zha, L., Cui, X., Yeh, Y., Liu, R., Jing, J., Shi, H., Chen, W., Hanover, J. A., Yin, J., et al. (2023) · Advanced Science · doi:10.1002/advs.202206068 · Cited by 63
Hotta, K., Kitamoto, T., Kitamoto, A., Ogawa, Y., Honda, Y., Kessoku, T., Yoneda, M., Imajo, K., Tomeno, W., Saito, S., et al. (2017) · Hepatology Research · doi:10.1111/hepr.12992 · Cited by 59
Campisano, S., la Colla, A. B., Echarte, S. M., & Chisari, A. N. (2019) · Nutrition Research Reviews · doi:10.1017/s0954422418000239 · Cited by 59
“Furthermore, nearly 70 000 methylated CpG sites in genes related to tissue repair and metabolic regulation have been found in these patients((55)).”
BackgroundCellular Senescence in Liver Disease and Regeneration
Ferreira-González, S., Rodrigo‐Torres, D., Gadd, V. L., & Forbes, S. J. (2021) · Seminars in Liver Disease · doi:10.1055/s-0040-1722262 · Cited by 60
Ma, J., Nano, J., Ding, J., Zheng, Y., Hennein, R., Liu, C., Speliotes, E. K., Huan, T., Song, C., Mendelson, M., et al. (2019) · Diabetes · doi:10.2337/db18-1193 · Cited by 61
“Previous studies using array-based methods have examined epigenome-wide DNA methylation patterns in liver samples of individuals with biopsy-proven NAFLD (5,6).”
BackgroundMartinez‐Uña, M., Varela‐Rey, M., Mestre, D., Fernández-Ares, L., Fresnedo, O., Fernández‐Ramos, D., Juan, V. G., Martín‐Guerrero, I., García‐Orad, Á., Luka, Z., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.10.019 · Cited by 58
“It has recently been described [25,26] that”
DNA methylation markers in the detection of hepatocellular carcinoma
Fu, S., Debes, J. D., & Boonstra, A. (2023) · European Journal of Cancer · doi:10.1016/j.ejca.2023.112960 · Cited by 57
Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis
Tian, Y., Mok, M. T. S., Yang, P., & Cheng, A. S. L. (2016) · Cancers · doi:10.3390/cancers8080076 · Cited by 55
“These findings support that epigenetic dysregulation is associated with NAFLD progression and HCC initiation [46].”
BackgroundResultKim, H.-J., Worsley, O., Yang, E., Purbojati, R. W., Liang, A. L., Tan, W. L. W., Moses, D., Hartono, S., Fan, V. S. K., Lim, T. K. H., et al. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03114-4 · Cited by 54
Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease
Arechederra, M., Recalde, M., Gárate‐Rascón, M., Fernández‐Barrena, M. G., Avila, M. A., & Berasain, C. (2021) · Cancers · doi:10.3390/cancers13061265 · Cited by 54
“NAFLD/NASH Differentially methylated CpG sigantures [53,55,56]”
BackgroundOkazaki, I., Noro, T., Tsutsui, N., Yamanouchi, E., Kuroda, H., Nakano, M., Yokomori, H., & Inagaki, Y. (2014) · Cancers · doi:10.3390/cancers6031220 · Cited by 55
“This discrepancy may be based in the etiology of HCC, because the hypothesis of Figure 2 is based on HBV- or HCV-related HCC while Figure 3a is NASH-related HCC.”
BackgroundInfluentialHigh fat diet and exercise lead to a disrupted and pathogenic DNA methylome in mouse liver
Zhou, D., Hlady, R. A., Schafer, M. J., White, T. A., Liu, C., Choi, J.-H., Miller, J. D., Roberts, L. R., LeBrasseur, N. K., & Robertson, K. D. (2016) · Epigenetics · doi:10.1080/15592294.2016.1261239 · Cited by 52
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
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