Molecular timer may hold the key to preventing preterm birth

Preterm birth remains a significant concern for expectant parents because it means that babies are born immature – before completing 37 weeks of gestation.

While human pregnancy typically lasts around 40 weeks, any parent can confirm that this figure is vague at best.

The timeline of birth is highly unpredictable. Babies arrive anytime between 38 and 42 weeks, with 10% of all births occurring preterm. Premature birth puts the newborns at risk of various complications.

A team of researchers at UC San Francisco has stumbled upon a significant finding: a molecular timekeeper in mice that possibly regulates the time of birth.

Intriguingly, this clock starts ticking right at the onset of pregnancy and operates within the uterus.

This discovery could hold immense potential for human pregnancies as it paves the way for diagnostic tests to pinpoint women who are at higher risk of preterm labor and who would benefit from interventions to prolong pregnancy.

Preterm birth: A global issue

Preterm birth is a prevalent issue worldwide, yet its underlying mechanism has puzzled experts for years.

“We hope our work can start to shed light on the underlying mechanism,” noted Dr. Adrian Erlebacher, a professor of laboratory medicine at UCSF who led the research.

“The new findings raise the possibility that preterm birth is triggered by things that happen much earlier in pregnancy than we expected.”

How DNA packaging influences pregnancy

Pregnancy triggers significant biological transformations in the female body, which result in the fluctuation of hundreds of genes within the uterus.

The researchers were particularly interested in studying KDM6B, a protein that assumes a regulatory role over gene activity and possibly over the genes responsible for the shift to labor.

This protein orchestrates gene expression by removing methyl chemical groups from histones – structures that organize and package DNA within cells.

Upon interaction with KDM6B, DNA becomes more receptive to other factors, thus accelerating the action of nearby genes.

Through their work, the team observed that blocking KDM6B resulted in prolonged mice pregnancies and delayed birth timings.

The quiet role of fibroblasts

While the initial suspicion was that KDM6B activates genes in the uterus’s epithelial cells late in pregnancy, detailed analyses revealed otherwise.

It was found that the protein’s effects on pregnancy length were instead linked to fibroblasts, the structural cells not typically considered in labor regulation.

Surprisingly, the regulation of these cells by KDM6B took place during the early days of pregnancy.

“This wasn’t something we anticipated, and it completely reshaped our understanding of the cell types and processes driving labor onset,” said Tara McIntyre, UCSF graduate student and lead author of the study.

Countdown to labor: Molecular timer in action

In-depth experiments showed that, soon after conception, methyl groups increase around certain genes in the uterine fibroblasts, which keeps these genes inactive and enables the uterus to support pregnancy.

As pregnancy progresses, the methylation levels on these histones gradually decrease, eventually activating the nearby genes related to events like labor. This progressive reduction functions as a timer.

“When histone methylation erodes enough, nearby genes flip on,” explained Erlebacher.

When the team blocked KDM6B, histones near a selection of genes accumulated excess methylation early in pregnancy.

This lead to delayed labor as the genes associated with birth were not activated in time despite methylation erosion.

Decoding preterm birth: A connection unearthed

Although the researchers did not directly analyze preterm births, the newly discovered molecular timer could potentially determine the length of pregnancy in humans.

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

If these molecular signals are disrupted in humans, they could be linked to preterm birth risk.

For instance, women commencing pregnancy with lower than usual levels of histone methylation could prematurely activate labor-related genes due to the swift erosion of methylation.

Erlebacher noted that previous studies on preterm birth have primarily focused on the period immediately before labor. However, these new findings suggest an emphasis on the early stages of pregnancy, opening up new avenues of research.

The full study was published in the journal Cell.

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