Abstract
SERine Protein INhibitor-A1 (SERPINA1) is an inducible blood cell gene coding for alpha1-antitrypsin (AAT), a plasma protease inhibitor whose circulating levels are raised during inflammation, infection and advanced pregnancy. DNA methylation has been suggested to play a role in SERPINA1 gene expression regulation in peripheral blood mononuclear cells (PBMCs). The methylation status of SERPINA1 in PBMCs is unknown. The aim of this study was to evaluate the methylation profile of the SERPINA1 promoter in PBMC. To this purpose PBMCs and serum were collected from healthy subjects (HS) (n = 75), including blood donors (BD) (n = 25), pregnant women at early pregnancy (EP) (n = 25), i.e., within the first trimester, and pregnant women at late pregnancy (LP) (n = 25), i.e., at the third trimester. DNA from PBMCs was treated with sodium bisulfite and PCR amplified for SERPINA1 gene promoter, followed by sequencing analyses. AAT serum levels were determined by ELISA test. SERPINA1 was found hypermethylated in 58.7% of HS. The prevalence of SERPINA1 hypermethylation was significantly higher in BD (68%) and EP (88%) than in LP (20%) (p < 0.01). The median serum AAT concentration was 1.07, 0.63, and 3.15 mg/ml in BD, EP, and LP, respectively (p < 0.05, BD and EP vs LP). This study indicates, for the first time, that SERPINA1 gene promoter is differentially methylated in PBMCs from HS. Likely, modulation of the methylation may be a novel epigenetic regulator mechanism of AAT expression in the PBMC of HS. Therefore, SERPINA1 gene promoter methylation may represent an epigenetic biomarker of PBMCs in healthy subjects.
Highlights
Serine Protease Inhibitor-A1 (SERPINA1) gene encodes for Alpha1-AntiTrypsin (AAT), the second most abundant circulating serum protein (Ferrarotti et al, 2012)
Using the bisulfite DNA treatment followed by PCR amplification and sequencing of the PCR products, the methylation profile of SERPINA1 gene promoter was assessed in peripheral blood mononuclear cells (PBMCs) from healthy subjects (HS) (n = 75), including blood donors (BD) (n = 25), early pregnancy (EP) (n = 25), and late pregnancy (LP) (n = 25)
The CpG6 site belonging to the CCGCCC-box consensus region showed methylation in 68% (17/25) BD, 88% (22/25) EP, and 20% (5/25) LP (BD vs LP p < 0.01; EP vs LP p < 0.0001, Figure 2, panels A,C)
Summary
Serine Protease Inhibitor-A1 (SERPINA1) gene encodes for Alpha1-AntiTrypsin (AAT), the second most abundant circulating serum protein (Ferrarotti et al, 2012). AAT is a protease inhibitor released from the hepatocytes constitutively (Miravitlles, 2012) It is primarily active in inflammation sites, where it plays a protective role for healthy cells adjacent to the inflamed tissue. How AAT could rise physiologically and maintain high levels for prolonged periods is not yet known. Regarding pregnancy, this is an important aspect given that lack of AAT increase exposes pregnant women and fetus to serious pathologies, such as pre-eclampsia and intrauterine fetal growth restriction (IUGR), which is the main cause of premature delivery and fetal mortality (KarowiczBilinska et al, 2007; Feng et al, 2016)
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