Research Project: EPIGENETIC REGULATION OF INFLAMMATION IN NAFLD
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Contributors
Funders
ID
EC.00076
Authors
Zeybel, Müjdat
Faculty Member
Publications
A proof-of-concept for epigenetic therapy of tissue fibrosis: inhibition of liver fibrosis progression by 3-Deazaneplanocin A
(Cell Press, 2017) Zeybel, Müjdat; Luli, Saimir; Sabater, Laura; Hardy, Timothy; Oakley, Fiona; Leslie, Jack; Page, Agata; Salvador, Eva Moran; Sharkey, Victoria; Tsukamoto, Hidekazu; Chu, David C. K.; Singh, Uma Sharan; Ponzoni, Mirco; Perri, Patrizia; Di Paolo, Daniela; Mendivil, Edgar J.; Mann, Jelena; Mann, Derek A.; School of Medicine; Yes; SCHOOL OF MEDICINE
The progression of fibrosis in chronic liver disease is dependent upon hepatic stellate cells (HSCs) transdifferentiating to a myofibroblast-like phenotype. This pivotal process is controlled by enzymes that regulate histone methylation and chromatin structure, which may be targets for developing anti-fibrotics. There is limited pre-clinical experimental support for the potential to therapeutically manipulate epigenetic regulators in fibrosis. In order to learn if epigenetic treatment can halt the progression of pre-established liver fibrosis, we treated mice with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep) in a naked form or by selectively targeting HSC-derived myofibroblasts via an antibody-liposome-DZNep targeting vehicle. We discovered that DZNep treatment inhibited multiple histone methylation modifications, indicative of a broader specificity than previously reported. This broad epigenetic repression was associated with the suppression of fibrosis progression as assessed both histologically and biochemically. The anti-fibrotic effect of DZNep was reproduced when the drug was selectively targeted to HSC-derived myofibroblasts. Therefore, the in vivo modulation of HSC histone methylation is sufficient to halt progression of fibrosis in the context of continuous liver damage. This discovery and our novel HSC-targeting vehicle, which avoids the unwanted effects of epigenetic drugs on parenchymal liver cells, represents an important proof-of-concept for epigenetic treatment of liver fibrosis.
DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease
(BioMed Central, 2016) Karahüseyinoğlu, Serçin; Zeybel, Müjdat; Vatansever, Sezgin; Hardy, Timothy; Sarı, Aysegül Akder; Çakalağaoğlu, Fulya; Avcı, Arzu; Zeybel, Gemma Louise; Bashton, Matthew; Mathers, John C.; Ünsal, Belkis; Mann, Jelena; Department of Molecular Biology and Genetics; School of Medicine; Yes; College of Sciences; SCHOOL OF MEDICINE
Background: Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B. Results: To identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium beadarrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies. Conclusions: Our findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. Cpg methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.
Ivacaftor and symptoms of extra-oesophageal reflux in patients with cystic fibrosis and G551D mutation
(Elsevier, 2017) Zeybel, Müjdat; Zeybel, Gemma L.; Pearson, Jeffrey P.; Krishnan, Amaran; Bourke, Stephen J.; Doe, Simon; Anderson, Alan; Faruqi, Shoaib; Morice, Alyn H.; Jones, Rhys; McDonnell, Melissa; Dettmar, Peter W.; Brodlie, Malcolm; Ward, Chris; School of Medicine; Yes; SCHOOL OF MEDICINE
Background: Extra-oesophageal reflux (EOR) may lead to microaspiration in patients with cystic fibrosis (CF), a probable cause of deteriorating lung function. Successful clinical trials of ivacaftor highlight opportunities to understand EOR in a real world study. Methods: Data from 12 patients with CF and the G551D mutation prescribed ivacaftor (150 mg bd) was collected at baseline, 6, 26 and 52 weeks. The changes in symptoms of EOR were assessed by questionnaire (reflux symptom index (RSI) and Hull airway reflux questionnaire (HARQ)). Results: Six patients presented EOR at baseline (RSI > 13; median 13; range 2-29) and 5 presented airway reflux (HARQ >13; median 12; range 3 to 33). Treatment with ivacaftor was associated with a significant reduction of EOR symptoms (P < 0.04 versus baseline) denoted by the reflux symptom index and Hull airway reflux questionnaire. Conclusion: Ivacaftor treatment was beneficial for patients with symptoms of EOR, thought to be a precursor to microaspiration.
Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease
(BMJ Publishing Group, 2017) Zeybel, Müjdat; Hardy, Timothy; Day, Christopher P.; Dipper, Christian; Masson, Steven; McPherson, Stuart; Henderson, Elsbeth; Tiniakos, Dina; White, Steve; French, Jeremy; Mann, Derek A.; Anstee, Quentin M.; Mann, Jelena; School of Medicine; Yes; SCHOOL OF MEDICINE
Objective Liver biopsy is currently the most reliable way of evaluating liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Its inherent risks limit its widespread use. Differential liver DNA methylation of peroxisome proliferator-activated receptor gamma (PPAR.) gene promoter has recently been shown to stratify patients in terms of fibrosis severity but requires access to liver tissue. The aim of this study was to assess whether DNA methylation of circulating DNA could be detected in human plasma and potentially used to stratify liver fibrosis severity in patients with NAFLD.
Design Patients with biopsy-proven NAFLD and age-matched controls were recruited from the liver and gastroenterology clinics at the Newcastle upon Tyne Hospitals NHS Foundation Trust. Plasma cell-free circulating DNA methylation of PPAR. was quantitatively assessed by pyrosequencing. Liver DNA methylation was quantitatively assessed by pyrosequencing NAFLD explant tissue, subjected to laser capture microdissection (LCM). Patients with alcoholic liver disease (ALD) were also subjected to plasma DNA and LCM pyrosequencing.
Results 26 patients with biopsy-proven NAFLD were included. Quantitative plasma DNA methylation of PPAR. stratified patients into mild (Kleiner 1-2) and severe (Kleiner 3-4) fibrosis (CpG1: 63% vs 86%, p<0.05; CpG2: 51% vs 65% p>0.05). Hypermethylation at the PPAR. promoter of plasma DNA correlated with changes in hepatocellular rather than myofibroblast DNA methylation. Similar results were demonstrated in patients with ALD cirrhosis.
Conclusions Differential DNA methylation at the PPAR. promoter can be detected within the pool of cell-free DNA of human plasma. With further validation, plasma DNA methylation of PPAR. could potentially be used to non-invasively stratify liver fibrosis severity in patients with NAFLD. Plasma DNA methylation signatures reflect the molecular pathology associated with fibrotic liver disease.
