Fibroblast cells (red) in the uterus of a mouse. Image: Omar Valdez/Erlebacher Lab
Research in pregnant mice suggests that epigenetic changes influence the timing of labour.
American biomedical scientists have identified a kind of molecular countdown clock in pregnant mice that determines when labour begins (Cell, 21 January). At the start of pregnancy, high levels of methylation keep certain genes inactive. Over the course of the pregnancy, those methylation levels gradually decline. The genes that are reactivated as a result trigger a cascade that ultimately initiates labour. Disruptions to this mechanism may lead to premature birth, the researchers speculate.
Shortly after fertilisation, the researchers observe a peak in the number of methyl groups on certain histones in uterine cells. The genes near these histones are less readily transcribed and therefore remain inactive. This epigenetic change occurs specifically in fibroblasts – connective tissue cells. What mechanism lies behind it remains a mystery to the researchers, but they do establish that methylation subsequently declines slowly. Eventually, methylation falls far enough for the previously inactive genes to resume their function. This presumably triggers a cascade that causes epithelial cells in the uterus to produce the hormone-like substance prostaglandin F2α, which gives the starting signal for labour.
The biomedical scientists identified the molecular countdown clock through their research into the protein KDM6B. This protein removes methyl groups from histones. When researchers prevented the production of KDM6B in the uterus, pregnant mice were found to have a longer gestation period. The lack of KDM6B presumably causes an unusually high level of methylation in uterine cells at the start of pregnancy, meaning it takes longer for methylation to decline sufficiently to initiate labour. The reverse – an abnormally low methylation level – may perhaps lead to premature birth. KDM6B appears, incidentally, to play no further role in the natural decline of methylation levels during pregnancy. Further research will need to establish which mechanism is responsible for that.
Although the precise workings of the countdown clock thus remain considerably unclear, the researchers are nonetheless hopeful about the practical applications of their findings. ‘Premature birth is a major problem worldwide, and for a long time nobody has really understood it. We hope our work can shed light on the underlying mechanism’, says last author Adrian Erlebacher in a press release. ‘The new findings suggest that premature birth is set in motion by things that happen much earlier in pregnancy than we had expected.’
At the start of pregnancy, high levels of methylation keep certain genes inactive