Epigenetic regulation of somatic angiotensin-converting enzyme by DNA methylation and histone acetylation

Abstract

Somatic angiotensin-converting enzyme (sACE) is crucial in cardiovascular homeostasis and displays a tissue-specific profile. Epigenetic patterns modulate genes expression and their alterations were implied in pathologies including hypertension. However, the influence of DNA methylation and chromatin condensation state on the expression of sACE is unknown. We examined whether such epigenetic mechanisms could participate in the control of sACE expression in vitro and in vivo. We identified two CpG islands in the human ace-1 gene 3 kb proximal promoter region. Their methylation abolished the luciferase activity of ace-1 promoter/reporter constructs transfected into human liver (HepG2), colon (HT29), microvascular endothelial (HMEC-1) and lung (SUT) cell lines (p < 0.001). Bisulphite sequencing revealed a cell-type specific basal methylation pattern of the ace-1 gene -1,466/+25 region. As assessed by RT-qPCR, inhibition of DNA methylation by 5-aza-2'-deoxycytidine and/or of histone deacetylation by trichostatin A highly stimulated sACE mRNA expression cell-type specifically (p < 0.001 vs. vehicle treated cells). In the rat, in vivo 5-aza-cytidine injections demethylated the ace-1 promoter and increased sACE mRNA expression in the lungs and liver (p = 0.05), but not in the kidney. In conclusion, the expression level of somatic ACE is modulated by CpG-methylation and histone deacetylases inhibition. The basal methylation pattern of the promoter of the ace-1 gene is cell-type specific and correlates to sACE transcription. DNMT inhibition is associated with altered methylation of the ace-1 promoter and a cell-type and tissue-specific increase of sACE mRNA levels. This study indicates a strong influence of epigenetic mechanisms on sACE expression.

Tissue-Specific Upregulation of Angiotensin-Converting Enzyme 1 in Spontaneously Hypertensive Rats Through Histone Code Modifications

“…28 Moreover, an HDAC inhibitor also induced Ace1 mRNA expression. 22 These data support the notion that histone modifications play a central role in the expression of Ace1 mRNA.…”

“…22 We also investigated Ace1 promoter methylation in various tissues of WKY rats and SHRs. The CpG island in the Ace1 promoter was almost unmethylated in all of the tissues studied in both WKY rats and SHRs ( Figure S2).…”

“…15,21 Moreover, somatic ACE expression is regulated by promoter methylation and histone acetylation in human cell lines and rat tissues. 22 We hypothesized that local tissue-specific upregulation of ACE1 in spontaneously hypertensive rats (SHRs) is caused by epigenetic changes, such as DNA methylation or histone code modifications in the Ace1 promoter region.…”

RAS Gene Polymorphisms and Renal Responsiveness to RAS Inhibition Therapy in Type 2 Diabetic Asian Indians

“…ACE I/D is in non coding region, which makes it unlikely to be a functional variant, but several studies suggest that it may be in close linkage disequilibrium (LD), with a quantitative trait loci (QTLs) controlling ACE levels [25,26]. Recent data also indicate that ACE expression may also be under epigenetic control [27].…”

The emerging role of epigenetics in cardiovascular disease

“…Furthermore, epigenetic studies in cardiovascular medicine revealed a significant number of modifications affecting the development and progression of CVD. In addition, epigenomics are also involved in cardiovascular risk factors such as smoking [Breitling et al 2011[Breitling et al , 2012Buro-Auriemma et al 2013], diabetes (see below), hypertension [Rivière et al 2011;Smolarek et al 2010] and age [Fuke et al 2004].…”