Loss of DNA methylation disrupts syncytiotrophoblast development: Proposed consequences of aberrant germline gene activation

DNA methylation is a repressive epigenetic modification that is essential for development and its disruption is widely implicated in disease. Yet, remarkably, ablation of DNA methylation in transgenic mouse models has limited impact on transcriptional states. Across multiple tissues and developmental contexts, the predominant transcriptional signature upon loss of DNA methylation is the de-repression of a subset of germline genes, normally expressed in gametogenesis. We recently reported loss of de novo DNA methyltransferase DNMT3B resulted in up-regulation of germline genes and impaired syncytiotrophoblast formation in the murine placenta. This defect led to embryonic lethality. We hypothesize that de-repression of germline genes in the Dnmt3b knockout underpins aspects of the placental phenotype by interfering with normal developmental processes. Specifically, we discuss molecular mechanisms by which aberrant expression of the piRNA pathway, meiotic proteins or germline transcriptional regulators may disrupt syncytiotrophoblast development. DNA methyltransferase 3B (Dnmt3b) knockout conceptuses show embryonic lethality due to impaired placental formation. These placental cells exhibit aberrant DNA methylation and de-repression of germline genes. We propose that germline gene expression disrupts normal placental development through altered transcript regulation, disrupted cell division, and spurious piRNA silencing of endogenous retroviruses.image

Automated summary

DNA methylation is an important epigenetic modification implicated in disease. Loss of DNA methylation mainly results in the de-repression of germline genes. This study found that knockout of the DNMT3B gene leads to up-regulation of germline genes and abnormal placental formation.