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| Status |
Public on Jul 25, 2019 |
| Title |
DNA Methylation Reprograms Metabolic Gene Expression in End-Stage Human Heart Failure |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
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| Summary |
Heart Failure (HF) is a complex clinical disease and leading cause of hospitalization in the United States. Although precision-based treatment options are ultimately preferred, understanding the common underlying features of HF is also needed to develop universal therapies that address its pathogenesis. Among the etiology-independent molecular changes known to occur in HF is a global shift in the heart’s metabolic substrate preference. Transcriptional reprogramming of the heart has been shown to mediate this metabolic switch towards glycolytic metabolism; however, the molecular machinery that reactivate dormant genes remain largely unknown. In the current study, we hypothesized that the cardiac epigenome regulates metabolism via alterations in DNA methylation.
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| Overall design |
We used paired whole-genome bisulfite sequencing and next-generation RNA sequencing of left ventricle tissue from 6 patients with end-stage heart failure and 3 non-failing donor hearts. Distribution of genome-wide methylation changes was localized to both the promoter-associated and gene body-associated CpG sites in HF relative to non-failing hearts. Gene set enrichment of genes coupled with promoter hyper-methylation identified suppression of oxidative metabolic pathways, whereas hypo-methylated promoters identified genes associated with anaerobic glycolysis. Furthermore, we found the Nuclear Respiratory Factor 1 (NRF1) binding site as a candidate DNA methylation-sensitive regulator of cardiac fatty acid oxidation. The current study therefore underscores the importance of DNA methylation as a molecular feature describes the failing hearts fetal-like metabolic preference.
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| Web link |
https://www.physiology.org/doi/abs/10.1152/ajpheart.00016.2019
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| Contributor(s) |
Pepin ME, Drakos S, Wende AR, Wever-Pinzon O |
| Citation(s) |
- Pepin ME, Drakos S, Ha CM, Tristani-Firouzi M et al. DNA methylation reprograms cardiac metabolic gene expression in end-stage human heart failure. Am J Physiol Heart Circ Physiol 2019 Oct 1;317(4):H674-H684. PMID: 31298559
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| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| F30 HL137240 |
GADD45B and Metabolic Memory in Diabetic Heart Failure |
UNIVERSITY OF ALABAMA AT BIRMINGHAM |
Mark Emile Pepin |
| R01 HL132067 |
Cellular Remodeling in Heart Failure and after LVAD Unloading |
UNIVERSITY OF UTAH |
Stavros George Drakos |
| R01 HL135121 |
Clinical and Metabolic Signature of Recovered Myocardium in Human Heart Failure |
UNIVERSITY OF UTAH |
Stavros George Drakos |
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| <button class="button" id="geo2r_button">Analyze with GEO2R</button> <button class="button" id="download_button">Download RNA-seq counts</button> |
| Submission date |
Dec 17, 2018 |
| Last update date |
Jul 25, 2019 |
| Contact name |
Mark Emile Pepin |
| E-mail(s) |
pepinme@gmail.com
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| Organization name |
University of Alabama at Birmingham
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| Department |
Biomedical Engineering
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| Lab |
Adam Wende Laboratory
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| Street address |
1825 University Blvd
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| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35294-2182 |
| Country |
USA |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA510407 |
| SRA |
SRP173647 |
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