Transition of LINE-1 DNA methylation status and altered expression in first and third trimester placentas.

Zhi-Ming He,Yi Lisa Hwa,Shi-Wen Jiang,Jinping Li,Brian Brost,Qun Fang,Victor Sanchez-Margalet

doi:10.1371/journal.pone.0096994

Abstract

DNA methylation plays a critical role in the regulation of gene expression, genomic DNA stability, cell proliferation, and malignant transformation. Common cellular features including fast tissue expansion, invasive growth, and active angiogenesis, have been noticed between placental development and tumorigenesis by many investigators. While the DNA hypomethylation and transcriptional activation of LINE-1 has been found to be a feature of tumorigenesis, it is not clear if similar changes could be involved in placental development. In this study, we assessed LINE-1 methylation in human placentas from different gestational ages and observed a significant decrease of LINE-1 methylation levels in third trimester placentas compared to first trimester placentas. Accompanying with this change is the significantly increased LINE-1 mRNA levels in third trimester placentas. Since no global DNA methylation change was detected between first and third trimesters, LINE-1 methylation changes appeared to be a specific epigenetic entity contributing to placental development. Indeed, further analyses showed that LINE-1 upregulation was correlated with higher levels of PCNA, suggesting a link between LINE-1 activation and fast proliferation of certain cellular components in third trimester placentas. Measurement of the DNMT1, DNMT3A, and DNMT3B expression found a significant reduction of DNMT3B between third and first trimesters, pointing to the possible involvement of this enzyme in the regulation of LINE-1 methylation. Taken together these results provided evidence for a dynamic temporal regulation of LINE-1 methylation and activation during placental development. These studies have laid a foundation for future investigation on the function of LINE-1 expression in human placenta under different patho-physiological conditions.

Highlights

In eukaryotic cells, approximately 1% of human genome, predominantly at the cytosine residues in the CpG dinucleotide sequences, is subject to methylation modification [1,2]
LINE-1 methylation in first and third trimester placentas LINE-1 DNA methylation levels at the 59UTR were determined in the first (1N) and third trimester (3N) human placentas with the use of COBRA method (Figure 2A)
In 7 out of 9 placentas (7/9), LINE-1 methylation levels were higher than 60.0% of the total DNA

Summary

Introduction

Approximately 1% of human genome, predominantly at the cytosine residues in the CpG dinucleotide sequences, is subject to methylation modification [1,2]. While some CpG dinucleotides concentrate in short genomic regions or CpG islands, most CpG sites distribute in a sporadic pattern along the intergenic and intronic regions, in some retroviral repeat sequences such as the long interspersed nuclear element (LINE-1), short interspersed nuclear element (SINE) and Sat2 [8]. Hypomethylation of these repeat sequences has been linked to pathological processes including tumorigenesis, abnormal placental function, birth defects, aging and other chronic diseases [9,10]

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Results

Conclusion