Abstract
BackgroundEarly pregnancy loss (EPL) is a frustrating clinical problem, whose mechanisms are not completely understood. DNA methylation, which includes maintenance methylation and de novo methylation directed by DNA methyltransferases (DNMTs), is important for embryo development. Abnormal function of these DNMTs may have serious consequences for embryonic development.MethodsTo evaluate the possible involvement of DNA methylation in human EPL, the expression of DNMT proteins and global methylation of DNA were assessed in villous or decidua from EPL patients. The association of maintenance methylation with embryo implantation and development was also examined.ResultsWe found that DNMT1 and DNMT3A were both expressed in normal human villous and decidua. DNMT1 expression and DNA global methylation levels were significantly down-regulated in villous of EPL. DNMT3A expression was not significantly changed in the EPL group compared to controls in either villous or decidua. We also found that disturbance of maintenance methylation with a DNMT1 inhibitor may result in a decreased global DNA methylation level and impaired embryonic development in the mouse model, and inhibit in vitro embryo attachment to endometrial cells.ConclusionsOur results demonstrate that defects in DNA maintenance methylation in the embryo, not in the mother, are associated with abnormal embryonic implantation and development. The findings of the current study provide new insights into the etiology of EPL.
Highlights
Pregnancy loss (EPL) is a frustrating clinical problem, whose mechanisms are not completely understood
Decreased DNMT1 expression level in human villous of Early pregnancy loss (EPL) Western blot analysis revealed that the DNMT1 expression level was significantly lower in villous of women with an EPL (n = 16) than controls (n = 16) (P = 0.023, Figure 1A), but there was no significant difference in DNMT1 expression in the decidua (P = 0.815, Figure 1A)
There were no significant differences in the expression level of DNMT3A in either villous or decidua between EPL (n = 16) and control (n = 16) specimens (P = 0.294 and P = 0.194, respectively, Figure 1B)
Summary
Pregnancy loss (EPL) is a frustrating clinical problem, whose mechanisms are not completely understood. Pregnancy loss (EPL) is one of the most common reproductive failures of human pregnancy It is characterized as high incidence, but the etiology is ambiguous. The global DNA epigenetic profile of the genome is dynamically reprogrammed during embryogenesis and the early development of the fetus [5] These dynamic processes are vital for the fertilization and histological differentiation of the embryo [6]. DNA methylation, as the primary regulator of hereditary information, occurs exclusively at CpG dinucleotides [7] These CpG islands are often among the promoter regions of genes and methylation of CpG islands results in transcriptional repression aberrant DNA methylation has been found to lead to abnormal embryonic development, birth malformations and other diseases, such as human carcinoma [8,9]
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