Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta

Abstract

In human post-natal somatic cells, low global levels of DNA methylation have been associated with the hypomethylation of several repetitive elements, a feature that has been proposed to be a surrogate epigenetic marker. These data, mainly derived from the analysis of cancer cells, suggest a potential association between loss of cellgrowth control and altered differentiation with hypomethylation of repetitive sequences. Partial hydatidiform moles (PHMs) can be used as an alternative model for investigating this association in a non-tumorigenic context. This gestational disease is characterized by abnormal overgrowth and differentiation of the placenta and spontaneous abortion. Here, we comprehensively analyse the DNA methylation of these trophoblastic tissues in both PHM and normal placenta at global and sequencespecific levels. Analysis of the global 5-methylcytosine content and immunohistochemistry indicate that PHM and normal placenta have identical global levels of DNA methylation. In contrast, bisulfite genomic sequencing shows that, whereas Alu, NBL2 and satellite 2 repetitive elements are equally methylated, LINE-1 sequences are hypermethylated in PHM tissues (B2-fold relative to normal placenta). Interestingly, altered demethylation is also found in triploid diandric embryos that originate from dispermic fertilization of an oocyte, a common event responsible for most PHMs. In conclusion, alterations of DNA methylation do not seem to be randomly distributed in PHM, as several repeated elements remain unaltered, whereas LINE-1 sequences are hypermethylated. In addition, our findings suggest that the hypomethylation of repetitive elements in cancer is directly linked to the neoplasic process and not a simple consequence of loss of growth control observed in most of the cancer cells.

Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences

“…6A). An increase of LINE-1 methylation has been seen previously in placentas (44) and in some specific loci in cancer (46). More importantly, we discovered that age-related hypomethylation was found at certain ages.…”

“…At present, IRSs are no longer considered junk DNA. Instead, several lines of evidence suggest that SINEs, LINEs, and LTRs are gene cis regulatory elements (12,17,26,44,45,47). Because SINEs, LINEs, and HERVs produce RNA, DNA methylation should alter their gene regulation activities.…”

Detection of global DNA methylation and paternally imprinted H19 gene methylation in preeclamptic placentas

“…44 Partial hydatidiform moles is characterized by placenta overgrowth, trophoblastic hyperplasia and abnormal or absent fetus. 45 These placenta phenotypes are to some extent similar to the observations in preeclamptic placenta where immature intermediate trophoblasts are over proliferating.…”

Influence of Prenatal Lead Exposure on Genomic Methylation of Cord Blood DNA

“…Lead exposure produces a wide spectrum of health outcomes, most notably neurocognitive and behavioral deficits in response to pre-and/or postnatal exposures (Needleman et al 1990). Lead exposure has also been associated with spontaneous abortions (Borja-Aburto et al 1999) and other adverse birth outcomes, such as preterm deliveries (Andrews et al 1994;Jelliffe-Pawlowski et al 2006) and low birth weight (Bellinger et al 1991;Gonzalez-Cossio et al 1997), which are risk factors for adverse health outcomes over the life course (Barker et al 1989;Rich-Edwards et al 1997). Recently, blood levels < 10 µg/dL during early childhood have been reported to confer reductions in IQ scores (Canfield et al 2003;Lanphear et al 2005), further questioning whether a threshold exists for the adverse consequences of lead exposure.…”