UCSF researchers discover molecular timer that regulates pregnancy length

UCSF researchers discover molecular timer that regulates pregnancy length

UCSF researchers discovered a molecular timer that activates in the first days of pregnancy and affects mice at birth.

A typical human pregnancy lasts 40 weeks, but most parents know that number is only a rough estimate.

Babies are born in a seemingly unpredictable timeline, with a normal pregnancy being between 38 and 42 weeks. And 10 percent of all births are premature, meaning they occur before 37 weeks of pregnancy, putting babies at risk of a variety of complications.

Now UC San Francisco researchers have discovered a molecular timer in mice that plays a role in control at birth. Surprisingly, the timer is activated in the first days of pregnancy and works inside the uterus.

If the same set of molecules is shown to be important in human pregnancies, it may lead to new tests to identify women at risk of premature births as well as interventions to delay them.

"Premature birth is a major problem around the world, and for a long time no one really understood it. We hope at UCSF and the lead author of the new paper, which appears on January 21st incell. “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 within the uterus increasing or decreasing.

Erlebacher and his lab group studied a protein called KDM6B, which regulates gene activity. They suspected that KDM6B might help regulate genes involved in the transition to work during pregnancy.

KDM6B remove methyl chemical groups from histones – structures that help organize and package DNA in cells. In response to KDM6B, DNA becomes more accessible to other factors that regulate gene expression and turn on the activity of nearby genes.

The team noticed that when they blocked KDM6B, pregnancies in the mice became longer and their babies were born later than usual.

Initially, scientists suspected that late in pregnancy, KDM6B must activate genes in uterine epithelial cells that produce hormones known to induce labor.

However, when they performed detailed analyzes 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 regulating work. Furthermore, KDM6B regulated these fibroblasts in the first days of pregnancy.

“Our results highlight a surprising role for uterine fibroblasts in regulating the timing of birth,” said Tara McIntyre, PhD, who led the work as a graduate student at UCSF. “We didn’t expect this, and it completely changed our understanding of the cell types and processes that drive the beginning of the work.”

A molecular timer?

Further experiments in mice showed that more methyl groups appear on histones near certain genes in uterine fibroblasts shortly after conception. In response, these genes remain inactive, allowing the uterus to support pregnancy.

As pregnancy progresses, methylation levels on these histones fade slowly and steadily, eventually reaching low enough for nearby genes - those associated with pregnancy events such as labor - to become activated. This erosion, which does not require KDM6B, acts as a timer.

Essentially what seems to be happening is that this timer landed early in the pregnancy and then progressively hangs down. If histone methylation is undermined enough, the genes in nearby genes will pass on. “

Adrian Erlebacher, MD, PhD, professor of laboratory medicine at UCSF

When the researchers blocked KDM6B, histones near certain genes accumulated too much methylation early in pregnancy. This increased “set point” meant that despite erosion, these genes were not activated in a timely manner, delaying work.

Signals could be linked to premature birth

While the new study did not examine premature births, the newly discovered molecular timer could help control pregnancy length in humans.

“The big question from here is whether the same processes are relevant in humans,” said Erlebacher. “If this is the case, can we use them to predict or control pregnancy length?”

If the newly studied molecular signals are disrupted in humans, they could be linked to the risk of preterm birth, his team hypothesizes. For example, some women may begin pregnancy with lower levels of histone methylation. and this could cause erosion of methylation to turn on work-related genes too quickly.

He adds that most preterm birth research has focused on the time immediately before a woman is born. The new findings point to much earlier stages of pregnancy as critical and could lead to new research efforts.

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