Diabetes changes gene expression but not DNA methylation in cardiac cells

Lother, Achim; Bondareva, Olga; Saadatmand, Ali R.; Pollmeier, Luisa; Härdtner, Carmen; Hilgendorf, Ingo; Weichenhan, Dieter; Eckstein, Volker; Plass, Christoph; Bode, Christoph; Backs, Johannes; Hein, Lutz; Gilsbach, Ralf

doi:10.1016/j.yjmcc.2020.11.004

Cited by 22 publications

(58 citation statements)

References 52 publications

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“…Corresponding with the fact that miR-340-5p overexpression increased cellular apoptosis in the heart tissue of diabetic mice, miR-340-5p has also been indicated as a suppressor for cancer cell proliferation and metastasis by enhancing their apoptosis [ 12 , 13 , 30 ]. Thus we hypothesized that candidate genes representing proposed targets of miR-340-5p would be accompanied by genes dysregulated in cardiomyocytes in DM and in the KEGG apoptosis pathway ( https://www.genome.jp/pathway/hsa04210 ) ( Figure 4(a) ) [ 31 ]. Under the strict screening conditions, we identified potential miR-340 target genes by bioinformatics analysis using the BiBiServ Tool, and 2 genes including Mcl-1 and Bcl2L11 were found (Table S3 ).…”

Section: Resultsmentioning

confidence: 99%

miR-340-5p Mediates Cardiomyocyte Oxidative Stress in Diabetes-Induced Cardiac Dysfunction by Targeting Mcl-1

Zhu

Yang

Zhou

et al. 2022

Oxidative Medicine and Cellular Longevity

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Diabetic cardiomyopathy (DCM) is initially characterized by early diastolic dysfunction, left ventricular remodeling, hypertrophy, and myocardial fibrosis, and it is eventually characterized by clinical heart failure. MicroRNAs (miRNAs), endogenous small noncoding RNAs, play significant roles in diabetes mellitus (DM). However, it is still largely unknown about the mechanism that links miRNAs and the development of DCM. Here, we aimed to elucidate the mechanism underlying the potential role of microRNA-340-5p in DCM in db/db mouse, which is a commonly used model of type 2 DM and diabetic complications that lead to heart failure. We first demonstrated that miR-340-5p expression was dramatically increased in heart tissues of mice and cardiomyocytes under diabetic conditions. Overexpression of miR-340-5p exacerbated DCM, which was reflected by extensive myocardial fibrosis and more serious dysfunction in db/db mice as represented by increased apoptotic cardiomyocytes, elevated ROS production, and impaired mitochondrial function. Inhibition of miR-340-5p by a tough decoy (TUD) vector was beneficial for preventing ROS production and apoptosis, thus rescuing diabetic cardiomyopathy. We identified myeloid cell leukemia 1 (Mcl-1) as a major target gene for miR-340-5p and showed that the inhibition of Mcl-1 was responsible for increased functional loss of mitochondria, oxidative stress, and cardiomyocyte apoptosis, thereby caused cardiac dysfunction in diabetic mice. In conclusion, our results showed that miR-340-5p plays a crucial role in the development of DCM and can be targeted for therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%

miR-340-5p Mediates Cardiomyocyte Oxidative Stress in Diabetes-Induced Cardiac Dysfunction by Targeting Mcl-1

Zhu

Yang

Zhou

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Analysis of heterocellular interactions in the diabetic heart suggests that the interplay between fibroblasts and monocytes is pivotal. A previous study showed that diabetes could change gene expression but not DNA methylation in cardiac cells (Lother et al, 2021).…”

Section: Dna Methylation and Diabetic Cardiomyopathymentioning

confidence: 96%

Research Progress on Epigenetics of Diabetic Cardiomyopathy in Type 2 Diabetes

Deng

Liao

Jian-pin

et al. 2021

Front. Cell Dev. Biol.

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Diabetic cardiomyopathy (DCM) is characterized by diastolic relaxation abnormalities in its initial stages and by clinical heart failure (HF) without dyslipidemia, hypertension, and coronary artery disease in its last stages. DCM contributes to the high mortality and morbidity rates observed in diabetic populations. Diabetes is a polygenic, heritable, and complex condition that is exacerbated by environmental factors. Recent studies have demonstrated that epigenetics directly or indirectly contribute to pathogenesis. While epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs, have been recognized as key players in the pathogenesis of DCM, some of their impacts remain not well understood. Furthering our understanding of the roles played by epigenetics in DCM will provide novel avenues for DCM therapeutics and prevention strategies.

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“…Enhancers can be annotated based on epigenetic marks, including chromatin accessibility, histone post-translational modifications and low DNA methylation 5,9 . Many studies including our studies assessing different cardiac cell-types show that regulatory elements are to a large degree lineage specific 10,11 . Enhancer variants therefore may act in a cell type-specific manner.…”

Section: Introductionmentioning

confidence: 93%

“…In contrast, highly similar interaction domains were detected for ABCA8. Furthermore genome-wide analysis of 200 CM-specific and 200 cardiac housekeeping genes expressed in main cardiac cell types 11 . This comparison revealed a significant higher number of promoterinteracting domains detectable in CM-specific Hi-C data as compared to cardiac tissue derived chromatin interaction data for CM-specific genes.…”

Section: Chromatin Interaction Analysis Of Sorted Human Cardiac Myocy...mentioning

confidence: 99%

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Decoding promoter-enhancer interactions in human cardiac myocytes

Bednarz

Laurette

Pedrosa

et al. 2022

Preprint

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The heart is a heterocellular organ consisting of several cell types including cardiomyocytes. Cell-type specific gene expression and response to stimuli is modulated by active distal regulatory elements termed enhancers. Cardiac enhancers are enriched for disease-associated variants and spatially interact with distal target promoters. However, enhancer-promoter interactions and spatial chromatin organization of human adult cardiac myocytes have not been analyzed so far limiting the interpretation of disease-associated regulatory elements in these cells. Here we generated high resolution spatial chromatin interaction data for atrial, left ventricular and failing human adult cardiac myocytes and identified cell-type specific interaction signatures. An integrative analysis with comprehensive epigenetic data reveals cardiac myocyte-specific, chamber-specific and disease-relevant enhancer-promoter interactions in cardiac myocytes. We further identified the cardiac disease risk association of promoter-interacting versus non-interacting enhancers and experimentally proofed the functional importance of enhancers harboring long QT risk loci. Our data shows that decoding cell type-specific regulatory elements and their interacting promoters provides insights into regulatory mechanisms essential for cell function and genetic risk factors as demonstrated here for human cardiac myocytes. This data will facilitate the interpretation of non-coding genetic risk factors in future genome-wide association studies. These data will allow predicting whether non-coding genetic variants promote disease in adult cardiac myocytes or not.

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Diabetes changes gene expression but not DNA methylation in cardiac cells

Cited by 22 publications

References 52 publications

miR-340-5p Mediates Cardiomyocyte Oxidative Stress in Diabetes-Induced Cardiac Dysfunction by Targeting Mcl-1

miR-340-5p Mediates Cardiomyocyte Oxidative Stress in Diabetes-Induced Cardiac Dysfunction by Targeting Mcl-1

Research Progress on Epigenetics of Diabetic Cardiomyopathy in Type 2 Diabetes

Decoding promoter-enhancer interactions in human cardiac myocytes

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