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| Status |
Public on Aug 22, 2018 |
| Title |
Genome-Wide DNA Methylation Encodes Cardiac Transcriptional Reprogramming in Human Ischemic Heart Failure [DNA Methylation] |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
|
| Summary |
Background – Epigenetic alterations are stable modifications to chromatin structure that occur in response to environmental cues such as hypoxia or altered nutrient delivery. DNA methylation is a well-established and dynamic DNA modification that contributes to the regulation of gene expression. In the current study, we test the hypothesize that ischemic heart failure is defined by a distinct signature of DNA methylation that corresponds with altered expression of genes involved in cardiac ventricular dysfunction.
Methods and Results – Using a methylation array, we quantified genome-wide DNA methylation of endomyocardial samples acquired from patients with ischemic (n = 6) or non-ischemic (n = 5) heart failure. RNA-sequencing analysis was performed in the same samples to identify transcriptomic changes (Fold Change > 1.5, Q < 0.05, FPKM > 2) associated with differential methylation (|Percent Change| > 5%, p < 0.05). Of the promoter-associated CpG Islands, which are well-established regions of negative transcriptional regulation, we identified a signature of robust hypermethylation. The methylation changes linked to significantly decreased transcripts included key fatty acid metabolic regulators (e.g. KLF15, AGPAT9, APOA1, and MXD4). Among the few hypomethylated and induced genes was PFKFB3, which encodes for the rate-limiting enzyme of glycolysis. Gene set enrichment analysis identified TGFβ as a nodal upstream regulator of the methylation changes, potentially supporting a role of DNA methylation in the increased fibrosis and apoptosis that accompanies ischemic heart failure.
Conclusions – Our data identify that the DNA methylation signature recapitulates the pathologic hallmarks of ischemic heart failure. Furthermore, we show that differential DNA methylation of CpG islands within the promoter depict alterations in metabolic substrate utilization known to occur in ischemic heart failure, and may govern a return to the fetal-like metabolic program.
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| Overall design |
Whole-Genome DNA Methylation analysis of left ventricle samples in 11 subjects with end-stage heart failure.
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| Contributor(s) |
Wende AR, Pepin ME |
| Citation(s) |
30089854, 33769919 |
| 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 |
| K99 HL111322 |
Mechanisms of glucose mediated cardiac mitochondrial dysfunction |
UNIVERSITY OF UTAH |
Adam Raymond Wende |
| R00 HL111322 |
Mechanisms of glucose mediated cardiac mitochondrial dysfunction |
UNIVERSITY OF ALABAMA AT BIRMINGHAM |
Adam Raymond Wende |
| R01 HL133011 |
Glucose-Mediated Remodeling of Cardiac DNA Methylation |
UNIVERSITY OF ALABAMA AT BIRMINGHAM |
Adam Raymond Wende |
| R56 HL133011 |
Glucose-Mediated Remodeling of Cardiac DNA Methylation |
UNIVERSITY OF ALABAMA AT BIRMINGHAM |
Adam Raymond Wende |
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| |
| Submission date |
Jan 11, 2018 |
| Last update date |
May 07, 2021 |
| Contact name |
Mark Emile Pepin |
| E-mail(s) |
pepinme@gmail.com
|
| Organization name |
University of Alabama at Birmingham
|
| Department |
Biomedical Engineering
|
| Lab |
Adam Wende Laboratory
|
| Street address |
1825 University Blvd
|
| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35294-2182 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL13534 |
Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482) |
|
| Samples (11)
|
| GSM2931611 |
genomic DNA from cardiac left ventricle A |
| GSM2931612 |
genomic DNA from cardiac left ventricle B |
| GSM2931613 |
genomic DNA from cardiac left ventricle C |
| GSM2931614 |
genomic DNA from cardiac left ventricle D |
| GSM2931615 |
genomic DNA from cardiac left ventricle E |
| GSM2931616 |
genomic DNA from cardiac left ventricle F |
| GSM2931617 |
genomic DNA from cardiac left ventricle G |
| GSM2931618 |
genomic DNA from cardiac left ventricle H |
| GSM2931619 |
genomic DNA from cardiac left ventricle I |
| GSM2931620 |
genomic DNA from cardiac left ventricle J |
| GSM2931621 |
genomic DNA from cardiac left ventricle K |
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| This SubSeries is part of SuperSeries: |
| GSE109097 |
Genome-Wide DNA Methylation Encodes Cardiac Transcriptional Reprogramming in Human Ischemic Heart Failure [DNA Methylation] |
|
| Relations |
| BioProject |
PRJNA429637 |
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