A typical human pregnancy lasts 40 weeks, but most parents know this number is only a rough estimate.
Babies are born on a seemingly unpredictable timeline, with a normal pregnancy ranging from 38 to 42 weeks. And 10 percent of all births are preterm, meaning they occur before 37 weeks of gestation, which puts babies at risk of a host of complications.
Now, UC San Francisco researchers have discovered a molecular timer in mice that plays a role in controlling when they give birth. Surprisingly, the timer is activated in the very first days of pregnancy and operates within the uterus.
If the same set of molecules is found to be important in human pregnancies, it could lead to new tests to identify women who are at risk of preterm labor, as well as interventions to delay it.
“Preterm birth is a huge problem around the world, and for a long time nobody has really understood it. We hope our work can start to shed light on the underlying mechanism,” said Adrian Erlebacher, M.D., Ph.D., a professor of laboratory medicine at UCSF, and the senior author of the new paper, which appears Jan. 21 in Cell. “The new findings raise the possibility that preterm birth is triggered by things that happen much earlier in pregnancy than we expected.”
DNA packaging during pregnancy
Throughout pregnancy, the female body undergoes massive biological shifts, with the activity of hundreds of genes going up or down within the uterus.
Erlebacher and his lab group were studying a protein called KDM6B that regulates gene activity. They suspected that during pregnancy, KDM6B could help regulate the genes involved in the transition to labor.
The team noticed that when they blocked KDM6B, pregnancies in the mice became longer, and their babies were born later than usual.
At first, the scientists suspected that, late in pregnancy, KDM6B activated genes in the uterus’s epithelial cells, which produce hormones known to trigger labor. But when they carried out detailed analyses on different cell types, they found that KDM6B’s effects on pregnancy length were tied to a different cell type called fibroblasts. These structural cells are not typically considered to play a role in the regulation of labor. Moreover, KDM6B regulated these fibroblasts during the first days of pregnancy.
“Our findings highlight a surprising role for uterine fibroblasts in regulating birth timing,” said Tara McIntyre, Ph.D., who led the work as a graduate student at UCSF. “This wasn’t something we anticipated, and it completely reshaped our understanding of the cell types and processes driving labor onset.”
A molecular timer?
KDM6B works by removing methyl chemical groups from histones — structures that help organize and package DNA within cells. In response to KDM6B, DNA becomes more accessible to other factors that regulate gene expression, turning on the activity of nearby genes.
Further experiments on mice revealed that shortly after conception, more methyl groups appear on histones near certain genes in uterine fibroblasts. In response, these genes remain inactive, which enables the uterus to support pregnancy.
Over the course of pregnancy, levels of methylation on these histones fade in a slow and steady way, eventually reaching low enough levels that the nearby genes — related to pregnancy events like labor — are activated. This erosion, which does not require KDM6B, functions as a timer.
“Essentially what appears to happen is this timer gets wound up right at the beginning of pregnancy, and then progressively winds down,” Erlebacher explained. “When histone methylation erodes enough, nearby genes flip on.”
When the researchers blocked KDM6B, histones near certain genes accumulated too much methylation early in pregnancy. This increased “setpoint” meant that, despite erosion, these genes were not activated on time, delaying labor.
Signals could be linked to preterm birth
While the study did not directly study preterm births, the newly discovered molecular timer could help control pregnancy length in humans.
“The big question from here is whether these same processes are relevant in humans,” Erlebacher said. “If they are, then can we use them to predict or control pregnancy length?”
If these newly studied molecular signals are disrupted in humans, they could be linked to preterm birth risk, his team hypothesizes. For instance, some women could begin pregnancy with lower than usual levels of histone methylation; and this could lead the erosion of the methylation to turn on labor-related genes too quickly.
He adds that most preterm birth research has focused on the time immediately before a woman goes into labor. The new results point toward much earlier stages of pregnancy as being critical, and it could lead to new research efforts.
Authors: Other authors include Omar Valdez, Nathan Kochhar, Brittany Davidson, Bushra Samad, M.S., Longhui Qiu, M.B., and Alexis Combes, Ph.D., all of UCSF; and Kenneth Hu, Ph.D., at M. D. Anderson Cancer Center.
Funding: Primary funding for the study was by the Burroughs Wellcome Fund Preterm Birth Initiative (1019789), the National Institutes of Health (R01AI150191, R01AI143187, F31HD106714), and the UCSF Bakar ImmunoX Initiative.
Disclosures: The authors have no competing interests.
