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. 2015:2015:459818.
doi: 10.1155/2015/459818. Epub 2015 Mar 30.

Methylation of promoter regions of genes of the human intrauterine Renin Angiotensin system and their expression

Shane D Sykes  1 , Carolyn Mitchell  2 , Kirsty G Pringle  1 , Yu Wang  1 , Tamas Zakar  3 , Eugenie R Lumbers  1
Affiliations

Methylation of promoter regions of genes of the human intrauterine Renin Angiotensin system and their expression

Shane D Sykes et al. Int J Endocrinol. 2015.

Abstract

The intrauterine renin angiotensin system (RAS) is implicated in placentation and labour onset. Here we investigate whether promoter methylation of RAS genes changes with gestation or labour and if it affects gene expression. Early gestation amnion and placenta were studied, as were term amnion, decidua, and placenta collected before labour (at elective caesarean section) or after spontaneous labour and delivery. The expression and degree of methylation of the prorenin receptor (ATP6AP2), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), and two proteases that can activate prorenin (kallikrein, KLK1, and cathepsin D, CTSD) were measured by qPCR and a DNA methylation array. There was no effect of gestation or labour on the methylation of RAS genes and CTSD. Amnion and decidua displayed strong correlations between the percent hypermethylation of RAS genes and CTSD, suggestive of global methylation. There were no correlations between the degree of methylation and mRNA abundance of any genes studied. KLK1 was the most methylated gene and the proportion of hypermethylated KLK1 alleles was lower in placenta than decidua. The presence of intermediate methylated alleles of KLK1 in early gestation placenta and in amnion after labour suggests that KLK1 methylation is uniquely dynamic in these tissues.

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Figures

Figure 1
Figure 1
The proportions of hypermethylated gene alleles for ACE, AGTR1, ATP6AP2, CTSD, and KLK1 and their corresponding mRNA abundances in amnion collected from early gestation (early, n = 8) and normal term pregnancies either by elective caesarean section prior to the onset of labour (C/S, n = 8) or after labour in women who had a spontaneous labour and vaginal delivery (SVB, n = 8). Significant differences were determined with Kruskal-Wallis tests using Dunn's multiple comparison test, with significant differences denoted by ∗ (adjusted P < 0.05). Data are presented as Tukey box plots with outliers shown as filled in circles. DNA methylation profiles could not be measured in early gestation for 1/8 ACE and KLK1 samples, from C/S for 1/8 ATP6AP2, 2/8 CTSD, and 5/8 KLK1 samples, and from SVB for 1/8 AGTR1, 4/8 ATP6AP2, 2/8 CTSD, and 5/8 KLK1 samples.
Figure 2
Figure 2
The proportions of hypermethylated alleles of ACE, AGTR1, ATP6AP2, CTSD, and KLK1 and the mRNA abundances of these genes isolated from decidua collected from normal term pregnancies either by elective caesarean section prior to the onset of labour (white bars, n = 8) or from women who had spontaneous labour and a vaginal delivery (grey bars, n = 8). Significant differences were determined using Mann-Whitney U tests, with significant differences denoted by ∗ (P < 0.05). Data are presented as Tukey box plots. DNA methylation profiles could not be detected in the absence of labour for 1/8 ACE, 1/8 AGTR1, 2/8 ATP6AP2, and 3/8 KLK1 samples and from after labour for 3/8 KLK1 samples.
Figure 3
Figure 3
The mRNA abundance of ACE, AGTR1, ATP6AP2, CTSD, and KLK1 in early and late gestation placentae (n = 4, resp.). Significant differences were determined using Mann-Whitney U tests, with significant differences denoted by ∗ (P < 0.05). Data are presented as Tukey box plots.
Figure 4
Figure 4
The proportions of hypermethylation in alleles of ACE, AGTR1, ATP6AP2, CTSD, and KLK1 and the mRNA abundance of these genes within amnion, decidua, and placenta collected from term pregnancies before the onset of labour. Significant differences were determined with Kruskal-Wallis tests using Dunn's multiple comparison test, with significant differences to amnion denoted by ∗ (P < 0.05) and ∗∗∗ (P < 0.001). Data are presented as Tukey box plots with outliers displayed as filled circles.
Figure 5
Figure 5
Spearman correlations between the proportions of hypermethylated RAS gene alleles within amnion samples isolated from early and late gestation and within decidua samples collected from before and after the onset of labour.
Figure 6
Figure 6
Spearman correlations between the proportion of hypermethylated CTSD alleles and the proportion of hypermethylated ACE and AGTR1 alleles in all amnion and decidua samples. ATP6AP2 was not correlated with CTSD.
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