Publications by authors named "Assam El-Osta"

166 Publications

Distinguishable DNA methylation defines disease susceptibility influenced by race and ethnicity.

Clin Epigenetics 2021 Oct 11;13(1):189. Epub 2021 Oct 11.

Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.

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http://dx.doi.org/10.1186/s13148-021-01180-9DOI Listing
October 2021

The Journal Club: Highlights on Recent Papers-9.

Noncoding RNA 2021 Sep 16;7(3). Epub 2021 Sep 16.

Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA.

We are delighted to share with you our ninth Journal Club and highlight some of the most interesting papers published recently [...].
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http://dx.doi.org/10.3390/ncrna7030058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482151PMC
September 2021

Prolonged Honeymoon Period in a Thai Patient with Adult-Onset Type 1 Diabetes Mellitus.

Case Rep Endocrinol 2021 1;2021:3511281. Epub 2021 Sep 1.

Diabetes and Thyroid Center, Theptarin Hospital, Bangkok, Thailand.

Objective: To describe a usual case of adult-onset T1DM with prolonged honeymoon period for more than 5 years.

Methods: Repeated mixed meal stimulation tests for a period of 6-12 months together with monitoring pancreatic autoantibodies and laboratory data were followed following the onset of diagnosis.

Results: We report a 24-year-old Thai patient with T1DM with sustained remission without antidiabetic medication for more than 5 years while maintaining low-carbohydrate intake and regular exercise. Repeated mixed meal stimulation tests for a period of 6-12 months revealed preserved beta-cell functions. Interestingly, repeated pancreatic autoantibodies at 5 years after diagnosis still showed positive anti-GAD, anti-IA2, and anti-ZnT8.

Conclusion: Restored beta-cell function with complete insulin withdrawal in new-onset T1DM has been reported in very few cases with some common factors as in our patient (low-carbohydrate intake with regular exercise). Delaying autoimmune activity by reducing metabolic load in newly diagnosed T1DM might play a role in maintaining the honeymoon period and could lead to an innovative therapeutic option in new-onset T1DM.
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http://dx.doi.org/10.1155/2021/3511281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429022PMC
September 2021

Editing the cardiac epigenome in broken heart syndrome.

Authors:
Assam El-Osta

Eur Heart J 2021 Sep 7. Epub 2021 Sep 7.

Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.

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http://dx.doi.org/10.1093/eurheartj/ehab632DOI Listing
September 2021

Targeting Methylglyoxal in Diabetic Kidney Disease Using the Mitochondria-Targeted Compound MitoGamide.

Nutrients 2021 Apr 25;13(5). Epub 2021 Apr 25.

Department of Diabetes, Central Clinical, School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, VIC 3004, Australia.

Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. In experimental diabetes, mitochondrial dysfunction in the kidney precedes the development of DKD. Reactive 1,2-dicarbonyl compounds, such as methylglyoxal, are generated from sugars both endogenously during diabetes and exogenously during food processing. Methylglyoxal is thought to impair the mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, a mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10 mg/kg/day) or a vehicle by oral gavage for 16 weeks. MitoGamide did not alter the blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis, and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signaling, immune system, respiratory electron transport, and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy.
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http://dx.doi.org/10.3390/nu13051457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145135PMC
April 2021

SAHA attenuates Takotsubo-like myocardial injury by targeting an epigenetic Ac/Dc axis.

Signal Transduct Target Ther 2021 Apr 20;6(1):159. Epub 2021 Apr 20.

Human Epigenetics Program, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1038/s41392-021-00546-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055670PMC
April 2021

Processed foods drive intestinal barrier permeability and microvascular diseases.

Sci Adv 2021 Mar 31;7(14). Epub 2021 Mar 31.

Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia.

Intake of processed foods has increased markedly over the past decades, coinciding with increased microvascular diseases such as chronic kidney disease (CKD) and diabetes. Here, we show in rodent models that long-term consumption of a processed diet drives intestinal barrier permeability and an increased risk of CKD. Inhibition of the advanced glycation pathway, which generates Maillard reaction products within foods upon thermal processing, reversed kidney injury. Consequently, a processed diet leads to innate immune complement activation and local kidney inflammation and injury via the potent proinflammatory effector molecule complement 5a (C5a). In a mouse model of diabetes, a high resistant starch fiber diet maintained gut barrier integrity and decreased severity of kidney injury via suppression of complement. These results demonstrate mechanisms by which processed foods cause inflammation that leads to chronic disease.
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http://dx.doi.org/10.1126/sciadv.abe4841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011970PMC
March 2021

Epigenetic evidence of an Ac/Dc axis by VPA and SAHA.

Clin Epigenetics 2021 03 20;13(1):58. Epub 2021 Mar 20.

Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.

Background: Valproic acid (VPA) is one of the most commonly used anti-epileptic drugs with pharmacological actions on GABA and blocking voltage-gated ion channels. VPA also inhibits histone deacetylase (HDAC) activity. Suberoylanilide hydroxamic acid is also a member of a larger class of compounds that inhibit HDACs. At the time of this article, there are 123 active international clinical trials for VPA (also known as valproate, convulex, divalproex, and depakote) and SAHA (vorinostat, zolinza). While it is well known that VPA and SAHA influence the accumulation of acetylated lysine residues on histones, their true epigenetic complexity remains poorly understood.

Results: Primary human cells were exposed to VPA and SAHA to understand the extent of histone acetylation (H3K9/14ac) using chromatin immunoprecipitation followed by sequencing (ChIP-seq). Because histone acetylation is often associated with modification of lysine methylation, we also examined H3K4me3 and H3K9me3. To assess the influence of the HDAC inhibitors on gene expression, we used RNA sequencing (RNA-seq). ChIP-seq reveals a distribution of histone modifications that is robust and more broadly regulated than previously anticipated by VPA and SAHA. Histone acetylation is a characteristic of the pharmacological inhibitors that influenced gene expression. Surprisingly, we observed histone deacetylation by VPA stimulation is a predominant signature following SAHA exposure and thus defines an acetylation/deacetylation (Ac/Dc) axis. ChIP-seq reveals regionalisation of histone acetylation by VPA and broader deacetylation by SAHA. Independent experiments confirm H3K9/14 deacetylation of NFκB target genes by SAHA.

Conclusions: The results provide an important framework for understanding the Ac/Dc axis by highlighting a broader complexity of histone modifications by the most established and efficacious anti-epileptic medication in this class, VPA and comparison with the broad spectrum HDAC inhibitor, SAHA.
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http://dx.doi.org/10.1186/s13148-021-01050-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981901PMC
March 2021

Sex-Specific Control of Human Heart Maturation by the Progesterone Receptor.

Circulation 2021 Apr 8;143(16):1614-1628. Epub 2021 Mar 8.

Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.

Background: Despite in-depth knowledge of the molecular mechanisms controlling embryonic heart development, little is known about the signals governing postnatal maturation of the human heart.

Methods: Single-nucleus RNA sequencing of 54 140 nuclei from 9 human donors was used to profile transcriptional changes in diverse cardiac cell types during maturation from fetal stages to adulthood. Bulk RNA sequencing and the Assay for Transposase-Accessible Chromatin using sequencing were used to further validate transcriptional changes and to profile alterations in the chromatin accessibility landscape in purified cardiomyocyte nuclei from 21 human donors. Functional validation studies of sex steroids implicated in cardiac maturation were performed in human pluripotent stem cell-derived cardiac organoids and mice.

Results: Our data identify the progesterone receptor as a key mediator of sex-dependent transcriptional programs during cardiomyocyte maturation. Functional validation studies in human cardiac organoids and mice demonstrate that the progesterone receptor drives sex-specific metabolic programs and maturation of cardiac contractile properties.

Conclusions: These data provide a blueprint for understanding human heart maturation in both sexes and reveal an important role for the progesterone receptor in human heart development.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055196PMC
April 2021

DNA methylation status correlates with adult β-cell regeneration capacity.

NPJ Regen Med 2021 Feb 12;6(1). Epub 2021 Feb 12.

Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.

The role of DNA methylation in β-cell neogenesis is poorly understood. We report that during the process of induced cell reprogramming, methylation content of the Ngn3 and Sox11 genes are diminished. These findings emphasise DNA methylation is a barrier in β-cell regeneration in adulthood, a well described pathophysiological phenomenon of major significance in explaining β-cell deficiency in diabetes in the adult pancreas.
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http://dx.doi.org/10.1038/s41536-021-00119-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881134PMC
February 2021

Valproic acid influences the expression of genes implicated with hyperglycaemia-induced complement and coagulation pathways.

Sci Rep 2021 01 25;11(1):2163. Epub 2021 Jan 25.

Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, The Alfred Medical Research and Education Precinct, Monash University, Melbourne, VIC, Australia.

Because the liver plays a major role in metabolic homeostasis and secretion of clotting factors and inflammatory innate immune proteins, there is interest in understanding the mechanisms of hepatic cell activation under hyperglycaemia and whether this can be attenuated pharmacologically. We have previously shown that hyperglycaemia stimulates major changes in chromatin organization and metabolism in hepatocytes, and that the histone deacetylase inhibitor valproic acid (VPA) is able to reverse some of these metabolic changes. In this study, we have used RNA-sequencing (RNA-seq) to investigate how VPA influences gene expression in hepatocytes. Interesting, we observed that VPA attenuates hyperglycaemia-induced activation of complement and coagulation cascade genes. We also observe that many of the gene activation events coincide with changes to histone acetylation at the promoter of these genes indicating that epigenetic regulation is involved in VPA action.
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http://dx.doi.org/10.1038/s41598-021-81794-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835211PMC
January 2021

Clinical Characteristics, Residual Beta-Cell Function and Pancreatic Auto-Antibodies in Thai people with Long-Standing Type 1 Diabetes Mellitus.

J ASEAN Fed Endocr Soc 2020 3;35(2):158-162. Epub 2020 Aug 3.

Diabetes and Thyroid Center, Theptarin Hospital, Bangkok, Thailand.

Objectives: To describe the characteristics of long-standing T1DM in Thai patients and assess residual beta-cell function with status of pancreatic autoantibodies.

Methodology: This is a cross-sectional study of Thai subjects with T1DM and disease duration ≥ 25 years seen at the Theptarin Hospital. Random plasma C-peptide and pancreatic auto-antibodies (Anti-GAD, Anti-IA2, and Anti-ZnT8) were measured. Patients who developed complications were compared with those who remained free of complications.

Results: A total of 20 patients (males 65%, mean age 49.4±12.0 years, BMI 22.5±3.1 kg/m, A1C 7.9±1.6%) with diabetes duration of 31.9±5.1 years were studied. Half of the participants remained free from any diabetic complications while the proportions reporting retinopathy, nephropathy, and neuropathy were 40%, 30%, and 15%, respectively. HDL cholesterol was significantly higher and triglyceride concentration significantly lower in patients who were free from diabetic nephropathy but not in those who were free from other complications. The prevalence rates of anti-GAD, anti-IA2, and anti-ZnT8 were 65%, 20%, and 10%, respectively. None of the patients who tested negative for both anti-GAD and anti-IA2 was positive for anti-ZnT8. Residual beta-cell function based on detectable random plasma C-peptide (≥ 0.1 ng/mL) and MMTT was found in only 3 patients (15%). There was no relationship between residual beta-cell function and protective effects of diabetic complications.

Conclusion: Endogenous insulin secretion persists in some patients with long-standing T1DM and half of longstanding T1DM in Thai patients showed no diabetic complications. HDL cholesterol was significantly higher and triglyceride concentration significantly lower in patients who were free from diabetic nephropathy.
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http://dx.doi.org/10.15605/jafes.035.02.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784202PMC
August 2020

DNA methylation patterns from peripheral blood separate coronary artery disease patients with and without heart failure.

ESC Heart Fail 2020 10 2;7(5):2468-2478. Epub 2020 Jul 2.

Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.

Aims: Natriuretic peptides are useful for diagnosis and prognostication of heart failure of any cause. Now, research aims to discover novel biomarkers that will more specifically define the heart failure phenotype. DNA methylation plays a critical role in the development of cardiovascular disease with the potential to predict fundamental pathogenic processes. There is a lack of data relating DNA methylation in heart failure that specifically focuses on patients with severe multi-vessel coronary artery disease. To begin to address this, we conducted a pilot study uniquely exploring the utility of powerful whole-genome methyl-binding domain-capture sequencing in a cohort of cardiac surgery patients, matched for the severity of their coronary artery disease, aiming to identify candidate peripheral blood DNA methylation markers of ischaemic cardiomyopathy and heart failure.

Methods And Results: We recruited a cohort of 20 male patients presenting for coronary artery bypass graft surgery with phenotypic extremes of heart failure but who otherwise share a similar coronary ischaemic burden, age, sex, and ethnicity. Methylation profiling in patient blood samples was performed using methyl-binding domain-capture sequencing. Differentially methylated regions were validated using targeted bisulfite sequencing. Gene set enrichment analysis was performed to identify differences in methylation at or near gene promoters in certain known Reactome pathways. We detected 567 188 methylation peaks of which our general linear model identified 68 significantly differentially methylated regions in heart failure with a false discovery rate <0.05. Of these regions, 48 occurred within gene bodies and 25 were located near enhancer elements, some within coding genes and some in non-coding genes. Gene set enrichment analyses identified 103 significantly enriched gene sets (false discovery rate <0.05) in heart failure. Validation analysis of regions with the strongest differential methylation data was performed for two genes: HDAC9 and the uncharacterized miRNA gene MIR3675. Genes of particular interest as novel candidate markers of the heart failure phenotype with reduced methylation were HDAC9, JARID2, and GREM1 and with increased methylation PDSS2.

Conclusions: We demonstrate the utility of methyl-binding domain-capture sequencing to evaluate peripheral blood DNA methylation markers in a cohort of cardiac surgical patients with severe multi-vessel coronary artery disease and phenotypic extremes of heart failure. The differential methylation status of specific coding genes identified are candidates for larger longitudinal studies. We have further demonstrated the value and feasibility of examining DNA methylation during the perioperative period to highlight biological pathways and processes contributing to complex phenotypes.
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http://dx.doi.org/10.1002/ehf2.12810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524212PMC
October 2020

Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis.

Circ Res 2020 09 22;127(7):877-892. Epub 2020 Jun 22.

Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Australia (A.J.M.).

Rationale: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear.

Objective: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis.

Methods And Results: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C subset, and neutrophils. Hematopoietic-restricted deletion of , , or its cognate receptor prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis.

Conclusions: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486277PMC
September 2020

The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan.

Cell Rep 2020 04;31(3):107548

Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and transcriptional reprogramming. Because of its previous associations with metabolic and transcriptional memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesize that the Set7 methyltransferase has an important role in trained immunity induced by β-glucan. Using pharmacological studies of human primary monocytes, we identify trained immunity-specific immunometabolic pathways regulated by Set7, including a previously unreported H3K4me1-dependent plasticity in the induction of oxidative phosphorylation. Recapitulation of β-glucan training in vivo additionally identifies Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as a key regulator of trained immunity, these findings provide mechanistic insight into sustained metabolic changes and underscore the importance of characterizing regulatory circuits of innate immune memory.
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http://dx.doi.org/10.1016/j.celrep.2020.107548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184679PMC
April 2020

Targeting Treatment Refractory by EZH2 Inhibition in Postural Tachycardia Syndrome.

Circ Res 2020 04 3;126(8):1058-1060. Epub 2020 Mar 3.

From the Epigenetics in Human Health and Disease Laboratory (H.K., A.W.K., J.O., A.E.-O.), Monash University, Melbourne, Australia.

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http://dx.doi.org/10.1161/CIRCRESAHA.119.315654DOI Listing
April 2020

Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease.

Circulation 2020 04 25;141(17):1393-1403. Epub 2020 Feb 25.

Heart Failure Research Group (D.M.K., W.A.S., H.A.J., D.H., B.G., A.F., F.Z.M.), Baker Heart and Diabetes Institute, Melbourne, Australia.

Background: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites.

Methods: One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg·d). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined.

Results: Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation.

Conclusions: The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043081DOI Listing
April 2020

Chinese Famine and the diabetes mellitus epidemic.

Nat Rev Endocrinol 2020 02;16(2):123

Peking University Diabetes Center, Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.

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http://dx.doi.org/10.1038/s41574-019-0300-9DOI Listing
February 2020

Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility.

Diabetes 2020 01 17;69(1):83-98. Epub 2019 Oct 17.

Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia

The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.
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http://dx.doi.org/10.2337/db19-0043DOI Listing
January 2020

Silencing Lysine-Specific Histone Demethylase 1 (LSD1) Causes Increased HP1-Positive Chromatin, Stimulation of DNA Repair Processes, and Dysregulation of Proliferation by Chk1 Phosphorylation in Human Endothelial Cells.

Cells 2019 10 7;8(10). Epub 2019 Oct 7.

Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.

The methylation of histone lysine residues modifies chromatin conformation and regulates the expression of genes implicated in cell metabolism. Lysine-specific demethylase 1 (LSD1) is a flavin-dependent monoamine oxidase that can demethylate mono- and dimethylated histone lysines 4 and 9 (H3K4 and H3K9). The removal of methyl groups from the lysine residues of histone and non-histone proteins was found to be an important regulatory factor of cell proliferation. However, its role has not been fully elucidated. In this study, we assessed LSD1-mediated cell cycle progression using a human endothelial cell model. The short hairpin RNA knockdown of LSD1 inhibits the G/M phase of cell cycle progression by checkpoint kinase 1 (Chk1) phosphorylation (S137). We observed elevated DNA damage, which was consistent with the increased detection of double-strand breaks as well as purines and pyrimidines oxidation, which accompanied the activation of ATR/ATRIP signaling by H2AXS139 phosphorylation. The irreversible pharmacological inhibition of LSD1 by 2-phenylcyclopropylamine (2-PCPA) inactivated its enzymatic activity, causing significant changes in heterochromatin and euchromatin conformation assessed by chromatin assembly factor 1 subunit A (CAF1A) and heterochromatin protein 1 isoform α and γ (HP1α/γ) immunofluorescence analysis. We conclude that the knockdown of LSD1 in endothelial cells leads to increased HP1-positive chromatin, the stimulation of DNA repair processes, and the dysregulation of proliferation machinery.
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http://dx.doi.org/10.3390/cells8101212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829479PMC
October 2019

RNA-seq-based identification of Star upregulation by islet amyloid formation.

Protein Eng Des Sel 2019 12;32(2):67-76

Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA 98018, USA.

Aggregation of islet amyloid polypeptide (IAPP) into islet amyloid results in β-cell toxicity in human type 2 diabetes. To determine the effect of islet amyloid formation on gene expression, we performed ribonucleic acid (RNA) sequencing (RNA-seq) analysis using cultured islets from either wild-type mice (mIAPP), which are not amyloid prone, or mice that express human IAPP (hIAPP), which develop amyloid. Comparing mIAPP and hIAPP islets, 5025 genes were differentially regulated (2439 upregulated and 2586 downregulated). When considering gene sets (reactomes), 248 and 52 pathways were up- and downregulated, respectively. Of the top 100 genes upregulated under two conditions of amyloid formation, seven were common. Of these seven genes, only steroidogenic acute regulatory protein (Star) demonstrated no effect of glucose per se to modify its expression. We confirmed this differential gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and also demonstrated the presence of STAR protein in islets containing amyloid. Furthermore, Star is a part of reactomes representing metabolism, metabolism of lipids, metabolism of steroid hormones, metabolism of steroids and pregnenolone biosynthesis. Thus, examining gene expression that is differentially regulated by islet amyloid has the ability to identify new molecules involved in islet physiology and pathology applicable to type 2 diabetes.
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http://dx.doi.org/10.1093/protein/gzz022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908819PMC
December 2019

Sex-Based Mhrt Methylation Chromatinizes MeCP2 in the Heart.

iScience 2019 Jul 27;17:288-301. Epub 2019 Jun 27.

Epigenetics in Human Health and Disease, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC 3004, Australia; Baker Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, 3/F Lui Che Woo Clinical Sciences Building, 30-32 Ngan Shing Street, Sha Tin, Hong Kong SAR; University College Copenhagen, Faculty of Health, Department of Technology, Biomedical Laboratory Science, Copenhagen, Denmark. Electronic address:

In the heart, primary microRNA-208b (pri-miR-208b) and Myheart (Mhrt) are long non-coding RNAs (lncRNAs) encoded by the cardiac myosin heavy chain genes. Although preclinical studies have shown that lncRNAs regulate gene expression and are protective for pathological hypertrophy, the mechanism underlying sex-based differences remains poorly understood. In this study, we examined DNA- and RNA-methylation-dependent regulation of pri-miR-208b and Mhrt. Expression of pri-miR-208b is elevated in the left ventricle of the female heart. Despite indistinguishable DNA methylation between sexes, the interaction of MeCP2 on chromatin is subject to RNase digestion, highlighting that affinity of the methyl-CG reader is broader than previously thought. A specialized procedure to isolate RNA from soluble cardiac chromatin emphasizes sex-based affinity of an MeCP2 co-repressor complex with Rest and Hdac2. Sex-specific Mhrt methylation chromatinizes MeCP2 at the pri-miR-208b promoter and extends the functional relevance of default transcriptional suppression in the heart.
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http://dx.doi.org/10.1016/j.isci.2019.06.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639684PMC
July 2019

Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals.

PLoS Genet 2019 06 19;15(6):e1008181. Epub 2019 Jun 19.

Molecular Virology Lab, Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.

The increasing worldwide prevalence of Hepatocellular carcinoma (HCC), characterized by resistance to conventional chemotherapy, poor prognosis and eventually mortality, place it as a prime target for new modes of prevention and treatment. Hepatitis C Virus (HCV) is the predominant risk factor for HCC in the US and Europe. Multiple epidemiological studies showed that sustained virological responses (SVR) following treatment with the powerful direct acting antivirals (DAAs), which have replaced interferon-based regimes, do not eliminate tumor development. We aimed to identify an HCV-specific pathogenic mechanism that persists post SVR following DAAs treatment. We demonstrate that HCV infection induces genome-wide epigenetic changes by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) for histone post-translational modifications that are epigenetic markers for active and repressed chromatin. The changes in histone modifications correlate with reprogramed host gene expression and alter signaling pathways known to be associated with HCV life cycle and HCC. These epigenetic alterations require the presence of HCV RNA or/and expression of the viral proteins in the cells. Importantly, the epigenetic changes induced following infection persist as an "epigenetic signature" after virus eradication by DAAs treatment, as detected using in vitro HCV infection models. These observations led to the identification of an 8 gene signature that is associated with HCC development and demonstrate persistent epigenetic alterations in HCV infected and post SVR liver biopsy samples. The epigenetic signature was reverted in vitro by drugs that inhibit epigenetic modifying enzyme and by the EGFR inhibitor, Erlotinib. This epigenetic "scarring" of the genome, persisting following HCV eradication, suggest a novel mechanism for the persistent pathogenesis of HCV after its eradication by DAAs. Our study offers new avenues for prevention of the persistent oncogenic effects of chronic hepatitis infections using specific drugs to revert the epigenetic changes to the genome.
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http://dx.doi.org/10.1371/journal.pgen.1008181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602261PMC
June 2019

Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia.

Epilepsia 2019 06 10;60(6):1091-1103. Epub 2019 May 10.

Epigenetics in Human Health and Disease, Central Clinical School, Monash University, Melbourne, Victoria, Australia.

Objectives: Focal cortical dysplasia (FCD) is a major cause of drug-resistant focal epilepsy in children, and the clinicopathological classification remains a challenging issue in daily practice. With the recent progress in DNA methylation-based classification of human brain tumors we examined whether genomic DNA methylation and gene expression analysis can be used to also distinguish human FCD subtypes.

Methods: DNA methylomes and transcriptomes were generated from massive parallel sequencing in 15 surgical FCD specimens, matched with 5 epilepsy and 6 nonepilepsy controls.

Results: Differential hierarchical cluster analysis of DNA methylation distinguished major FCD subtypes (ie, Ia, IIa, and IIb) from patients with temporal lobe epilepsy patients and nonepileptic controls. Targeted panel sequencing identified a novel likely pathogenic variant in DEPDC5 in a patient with FCD type IIa. However, no enrichment of differential DNA methylation or gene expression was observed in mechanistic target of rapamycin (mTOR) pathway-related genes.

Significance: Our studies extend the evidence for disease-specific methylation signatures toward focal epilepsies in favor of an integrated clinicopathologic and molecular classification system of FCD subtypes incorporating genomic methylation.
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http://dx.doi.org/10.1111/epi.14934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635741PMC
June 2019

Evaluation of genomic methylation indices in juvenile myoclonic epilepsy.

Authors:
Assam El-Osta

Epilepsia 2019 05;60(5):e37-e39

Epigenetics in Human Health and Disease, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, Australia.

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http://dx.doi.org/10.1111/epi.14740DOI Listing
May 2019

Digital expression explorer 2: a repository of uniformly processed RNA sequencing data.

Gigascience 2019 04;8(4)

Epigenetics in Human Health and Disease, Central Clinical School, Faculty of Medicine, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia.

Background: RNA sequencing (RNA-seq) is an indispensable tool in the study of gene regulation. While the technology has brought with it better transcript coverage and quantification, there remain considerable barriers to entry for the computational biologist to analyse large data sets. There is a real need for a repository of uniformly processed RNA-seq data that is easy to use.

Findings: To address these obstacles, we developed Digital Expression Explorer 2 (DEE2), a web-based repository of RNA-seq data in the form of gene-level and transcript-level expression counts. DEE2 contains >5.3 trillion assigned reads from 580,000 RNA-seq data sets including species Escherichia coli, yeast, Arabidopsis, worm, fruit fly, zebrafish, rat, mouse, and human. Base-space sequence data downloaded from the National Center for Biotechnology Information Sequence Read Archive underwent quality control prior to transcriptome and genome mapping using open-source tools. Uniform data processing methods ensure consistency across experiments, facilitating fast and reproducible meta-analyses.

Conclusions: The web interface allows users to quickly identify data sets of interest using accession number and keyword searches. The data can also be accessed programmatically using a specifically designed R package. We demonstrate that DEE2 data are compatible with statistical packages such as edgeR or DESeq. Bulk data are also available for download. DEE2 can be found at http://dee2.io.
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http://dx.doi.org/10.1093/gigascience/giz022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446219PMC
April 2019

Author Correction: Epidemic T2DM, early development and epigenetics: implications of the Chinese Famine.

Nat Rev Endocrinol 2019 05;15(5):312

Peking University Diabetes Center, Director of Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.

In the version of this article published online and in print, there was a mistake in the legend of Fig. 2 regarding the descriptions of the red and blue colours in the Figure. The text should have read 'The blue and red colours represent regions (provinces) with wheat and rice as the staple food, respectively.' This has now been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41574-019-0199-1DOI Listing
May 2019

Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions.

Nucleic Acids Res 2019 03;47(5):2455-2471

Molecular Virology Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.

Hepatitis C virus (HCV) infection is the leading cause of chronic hepatitis, which often results in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV possesses an RNA genome and its replication is confined to the cytoplasm. Yet, infection with HCV leads to global changes in gene expression, and chromosomal instability (CIN) in the host cell. The mechanisms by which the cytoplasmic virus affects these nuclear processes are elusive. Here, we show that HCV modulates the function of the Structural Maintenance of Chromosome (SMC) protein complex, cohesin, which tethers remote regions of chromatin. We demonstrate that infection of hepatoma cells with HCV leads to up regulation of the expression of the RAD21 cohesin subunit and changes cohesin residency on the chromatin. These changes regulate the expression of genes associated with virus-induced pathways. Furthermore, siRNA downregulation of viral-induced RAD21 reduces HCV infection. During mitosis, HCV infection induces hypercondensation of chromosomes and the appearance of multi-centrosomes. We provide evidence that the underlying mechanism involves the viral NS3/4 protease and the cohesin regulator, WAPL. Altogether, our results provide the first evidence that HCV induces changes in gene expression and chromosome structure of infected cells by modulating cohesin.
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http://dx.doi.org/10.1093/nar/gkz052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412124PMC
March 2019

Epigenetics, cardiovascular disease, and cellular reprogramming.

J Mol Cell Cardiol 2019 03 25;128:129-133. Epub 2019 Jan 25.

Department of Diabetes, Epigenetics in Human Health and Disease Laboratory, Monash University, Melbourne, VIC, Australia; Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.

Under the seeming disorder of "junk" sequences the last decade has seen developments in our understanding of non-coding RNA's (ncRNAs). It's a complex revised order and nowhere is this more relevant than in the developing heart whereby old rules have been set aside to make room for new ones. The development of the mammalian heart has been studied at the genetic and cellular level for several decades because these areas were considered ideal control points. As such, detailed mechanisms governing cell lineages are well described. Emerging evidence suggests a complex new order regulated by epigenetic mechanisms mark cardiac cell lineage. Indeed, molecular cardiologists are in the process of shedding light on the roles played by ncRNAs, nucleic acid methylation and histone/chromatin modifications in specific pathologies of the heart. The aim of this article is to discuss some of the recent advances in the field of cardiovascular epigenetics that are related to direct cell reprogramming and repair. As such, we explore ncRNAs as nodes regulating signaling networks and attempt to make sense of regulatory disorder by reinforcing the importance of epigenetic components in the developmental program.
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http://dx.doi.org/10.1016/j.yjmcc.2019.01.019DOI Listing
March 2019

Galectin-3 deficiency ameliorates fibrosis and remodeling in dilated cardiomyopathy mice with enhanced Mst1 signaling.

Am J Physiol Heart Circ Physiol 2019 01 2;316(1):H45-H60. Epub 2018 Nov 2.

Baker Heart and Diabetes Institute , Melbourne, Victoria , Australia.

Dilated cardiomyopathy (DCM) is a major cause of heart failure without effective therapy. Fibrogenesis plays a key role in the development of DCM, but little is known of the expression of the profibrotic factor galectin-3 (Gal-3) and its role in DCM pathophysiology. In a mouse DCM model with transgenic (TG) overexpression of mammalian sterile 20-like kinase 1 (Mst1), we studied Gal-3 expression and effects of the Gal-3 inhibitor modified citrus pectin (MCP) or Gal-3 gene knockout (KO). Gal-3 deletion in TG mice (TG/KO) was achieved by crossbreeding Mst1-TG mice with Gal-3 KO mice. The DCM phenotype was assessed by echocardiography and micromanometry. Cardiac expression of Gal-3 and fibrosis were determined. The cardiac transcriptome was profiled by RNA sequencing. Mst1-TG mice at 3-8 mo of age exhibited upregulated expression of Gal-3 by ~40-fold. TG mice had dilatation of cardiac chambers, suppressed left ventricular (LV) ejection fraction, poor LV contractility and relaxation, a threefold increase in LV collagen content, and upregulated fibrotic genes. Four-month treatment with MCP showed no beneficial effects. Gal-3 deletion in Mst1-TG mice attenuated chamber dilatation, organ congestion, and fibrogenesis. RNA sequencing identified profound disturbances by Mst1 overexpression in the cardiac transcriptome, which largely remained in TG/KO hearts. Gal-3 deletion in Mst1-TG mice, however, partially reversed the dysregulated transcriptional signaling involving extracellular matrix remodeling and collagen formation. We conclude that cardiac Mst1 activation leads to marked Gal-3 upregulation and transcriptome disturbances in the heart. Gal-3 deficiency attenuated cardiac remodeling and fibrotic signaling. NEW & NOTEWORTHY We found in a transgenic mouse dilated cardiomyopathy (DCM) model a pronounced upregulation of galectin-3 in cardiomyocytes. Galectin-3 gene deletion reduced cardiac fibrosis and fibrotic gene profiles and ameliorated cardiac remodeling and dysfunction. These benefits of galectin-3 deletion were in contrast to the lack of effect of treatment with the galectin-3 inhibitor modified citrus pectin. Our study suggests that suppression of galectin-3 mRNA expression could be used to treat DCM with high cardiac galectin-3 content.
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http://dx.doi.org/10.1152/ajpheart.00609.2018DOI Listing
January 2019
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