Distinct epigenomic features in end-stage failing human hearts.
BACKGROUND
The epigenome refers to marks on the genome, including DNA methylation and histone modifications, that regulate the expression of underlying genes. A consistent profile of gene expression changes in end-stage cardiomyopathy led us to hypothesize that distinct global patterns of the epigenome may also exist.


RESULTS
We constructed genome-wide maps of DNA methylation and histone-3 lysine-36 trimethylation (H3K36me3) enrichment for cardiomyopathic and normal human hearts. More than 506 Mb sequences per library were generated by high-throughput sequencing, allowing us to assign methylation scores to ≈28 million CG dinucleotides in the human genome. DNA methylation was significantly different in promoter CpG islands, intragenic CpG islands, gene bodies, and H3K36me3-enriched regions of the genome. DNA methylation differences were present in promoters of upregulated genes but not downregulated genes. H3K36me3 enrichment itself was also significantly different in coding regions of the genome. Specifically, abundance of RNA transcripts encoded by the DUX4 locus correlated to differential DNA methylation and H3K36me3 enrichment. In vitro, Dux gene expression was responsive to a specific inhibitor of DNA methyltransferase, and Dux siRNA knockdown led to reduced cell viability.


CONCLUSIONS
Distinct epigenomic patterns exist in important DNA elements of the cardiac genome in human end-stage cardiomyopathy. The epigenome may control the expression of local or distal genes with critical functions in myocardial stress response. If epigenomic patterns track with disease progression, assays for the epigenome may be useful for assessing prognosis in heart failure. Further studies are needed to determine whether and how the epigenome contributes to the development of cardiomyopathy.
Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Level 6, Hills Rd, Cambridge, CB2 0QQ UK.
Mehregan
M
Movassagh
Mun-Kit
MK
Choy
David A
DA
Knowles
Lina
L
Cordeddu
Syed
S
Haider
Thomas
T
Down
Lee
L
Siggens
Ana
A
Vujic
Ilenia
I
Simeoni
Chris
C
Penkett
Martin
M
Goddard
Pietro
P
Lio
Martin R
MR
Bennett
Roger S-Y
RS
Foo
D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology; D018450:Disease Progression; D057890:Epigenomics; D005786:Gene Expression Regulation / Q000502:physiology*; D006333:Heart Failure / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D011379:Prognosis
C121257:DUX4L1 protein, human; D006657:Histones; D018398:Homeodomain Proteins