Due Dates: How a Molecular Timer May Set the Start of Labor
By Alessandra Veinbachs
Childbirth - the end of pregnancy and the beginning of life outside the womb - has long fascinated expecting parents, medical dramas, and biologists alike.
This fascination has driven scientists to work out the very last steps in the process. Just before delivery, cells in the uterus begin producing a molecule called PGF2ɑ. This triggers the production of a protein that breaks down progesterone (P4). As P4 levels fall, the muscular walls of the uterus begin to contract, pushing the fetus out.
It is crucial that this process does not start too early or too late, yet despite its central role in the mammalian lifecycle, we don’t know what triggers this final cascade of events in the first place. Recently, researchers in Dr. Adrian Erlebacher’s lab at UCSF wondered if gene regulation might act as a molecular timer, helping time the length of pregnancy.
Although every cell in the body contains the same DNA, different cell types carry out different functions by expressing different genes. These genes contain the instructions for making proteins, the executors of cellular functions. The precise timing of gene expression is crucial for ensuring that biological processes happen when they’re supposed to and is regulated by programs such as histone modifications. In the nucleus of the cell, DNA is tightly coiled around proteins called histones, like thread wrapped around a spool. A modification called H3K27me3, added by histone methyltransferases, stops the expression of genes wrapped around that histone. Removing this mark, via proteins such as histone demethylase KDM6B, allows those genes to be expressed.
To test the role of KDM6B (and gene regulation more generally) in determining labor timing, the researchers created mice that lacked the histone demethylase KDM6B in cells of the uterus called uterine fibroblasts. They found that, compared to control mice, those lacking KDM6B had a delayed drop in P4 and gave birth several days later. This suggested that without KDM6B, the uterus was unable to activate the gene program required to initiate labor at the proper time.
The team then turned to a technique called CUT&RUN to examine the interactions between histone modifications and DNA. Using this technique, they found that mice lacking KDM6B accumulated more H3K27me3 marks in early pregnancy. Surprisingly, establishment of a pregnancy wasn’t required to start the process of setting H3K27me3 levels; mating alone started this program.
To understand how these early changes in histone modifications affect gene expression throughout pregnancy, the team tracked the expression of genes located near the altered H3K27me3 marks. While some of the early H3K27me3 marks were removed over time by other means, the absence of KDM6B led to persistent silencing and dysregulation of key genes required later in pregnancy. Importantly, several of these genes overlap with those known to be activated in the human uterus during labor. This means that a gene regulation program set early may help prepare the uterus for birth weeks later.
These findings open up new questions about how the timing of labor is coordinated within the uterus and across organ systems. For one, the researchers showed that the KDM6B-dependent gene regulation program begins right after mating - even before a pregnancy is established. But what signals from mating trigger this program? And what happens to the histone marks over time if a pregnancy is not established?
While this study focused on uterine fibroblasts and a single demethylase, KDM6B, labor involves complex coordination between several different cell types. Do other cells have their own molecular timers or do they rely on signals from uterine fibroblasts, which function as timekeepers? Additionally, what roles do other histone methyltransferases or histone demethylases play? For example, mice lacking KDM6A experienced early pregnancy failure, though why this happens is unclear. And although H3K27me3 marks are eventually eroded later in pregnancy, the mechanisms controlling this process remain elusive.
Premature birth remains a major cause of infant illness and death worldwide. Without knowing how labor is initiated normally, we can’t begin to understand what causes labor to happen too early or too late or develop strategies to correct disruptions in labor timing. This study offers new insights into how pregnancy length may be regulated at the level of gene expression and suggests that the molecular timer may start ticking earlier than previously appreciated.
A link to the full publication can be found here: https://pubmed.ncbi.nlm.nih.gov/39842437/