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Combined epigenomic and genomic approach to hypertension
Author(s) -
Michalkiewicz Mieczyslaw,
Michalkiewicz Teresa,
MacGillis Kyle
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.968.2
Subject(s) - dna methylation , epigenetics , methylated dna immunoprecipitation , epigenomics , cpg site , biology , bisulfite sequencing , epigenome , chromatin immunoprecipitation , genetics , gene , methylation , genome , microbiology and biotechnology , genomic dna , promoter , gene expression
DNA methylation of cytosine (CpG) is the best understood epigenetic information that may silence the gene directly by inhibiting binding of transcription factors or indirectly by chromatin modification. This epigenetic variation may underlie hypertension and in fact it may explain the late onset, progressive and quantitative nature of this disease better than variation in DNA sequence. We hypothesized that epigenetic variations in CpG methylation are of genetic origin and contribute to the development of hypertension in Dahl salt‐sensitive (SS) rats. Genome‐wide methylation patterns in the SS and normotensive Brown Norway (BN) rats were assessed in a high throughput manner by combining methylated DNA immunoprecipitation with a competitive hybridization on a high‐density microarray (NimbleGene) covering 2.7 kb promoter area of 21,600 genes. More than 1,000 targets were hypermethylated in the kidney of SS rats as compared to BN. The hearts methylomes were more similar between the strains. Hypermethylation of the SS genome was confirmed by LUMA. We then zoomed in on the known hypertension QTLs, congenic areas and further narrowed down the hypermethylated targets, which included renin. Using pyrosequencing of bisulfite converted DNA we determined quantitatively that comparing to BN, over ten CpGs were significantly (p<0.05) hypermethylathed in the renin promoter of the SS kidney, consistent with the reduced renin expression in this strain. Thus, we identified genome‐wide differentially methylated genomic regions between hypertensive and normotensive genomes and suggest that epigenetic mechanism may underlie the salt sensitive hypertension. Support: NIH HL 082798, AHW MCW.