A recent study, performed by the March of Dimes Prematurity Research Center and headed by scientists from the University of Chicago, has detected new genetic markers linked to the duration of gestation. These latest findings shed new light on the possible risk factors for preterm birth.
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In an association between numerous laboratories and financially supported through March of Dimes, the researchers set out to plot crucial gene regulatory areas and new genetic markers that are pertinent to preterm birth.
Addressing the absence of functional genomics information in pregnancy-related tissue types represented the first challenge for the team.
When you're studying a disease, there are typically a lot of genetic and tissue resources available in public databases. But pregnancy related conditions, like preterm birth, get much less attention or funding, and as a result, pregnancy-relevant tissues are not well represented in those databases.”
Carole Ober, PhD, Study Co-Senior Author and Chair of Human Genetics, The University of Chicago Medical Center
Published in the Science Advances journal on December 2nd, 2020, the article targeted decidualized cells that were obtained from the endometrial cells fixed to the placenta. During the latter half of the menstrual cycle, decidualized cells line the uterus and prepare it for implantation and they also support the growth and development of the fetus and placenta for the duration of pregnancy.
The researchers obtained placental tissue offered by patients who had given birth, and tehn separated the decidualized cells in the laboratory. Genetic examination of such cells revealed a pair of new candidate preterm birth genes, called GATA2 and HAND2.
“These genes are both important transcription factors that regulate the expression of several other genes. HAND2 mediates the effect of progesterone on the uterine epithelium while GATA2 is involved in stem cell maintenance,” stated Ivy Aneas, PhD, the co-first author of the study and a research associate professor of human genetics at The University of Chicago Medical Center.
The two processes and the genes that regulate them are known to be crucial for embryo implantation and endometrial decidualization.
The fact that we identified a link between these two genes and the duration of gestation suggests that their roles in pregnancy may be more important than previously anticipated.”
Noboru Sakabe, PhD, Study Co-First Author and Staff Scientist, The University of Chicago Medical Center
Interpreting the role of these genes in the duration of pregnancy could be crucial for designing new prevention strategies against preterm birth.
“Researchers have recognized a number of factors that can lead to preterm birth, ranging from environmental to infectious disease and beyond, but what is vexing is that we haven't been successful in preventing it,” stated Marcelo Nobrega, MD, PhD, the co-senior author of the study and professor of human genetics at The University of Chicago Medical Center..
Dr Nobrega continued, “Our research took a look at the genetics and allowed us to pull out some links that might illuminate genetic pathways and signaling molecules involved in the decidualization process, which in turn might provide new targets for therapies.”
The investigators leveraged their combined know-how in genomics, human genetics, and statistical analysis to integrate the data collected from human endometrial cells in the laboratory with the data available from prevalent genome-wide association studies (GWAS). Their goal was to identify the major genetic changes that may be associated with preterm birth.
Only six or seven genomic regions have been linked to preterm birth and gestational length. We don't know which genes are involved or how that influences cell function and risk of preterm birth.”
Xin He, PhD, Study Co-Senior Author and Assistant Professor of Human Genetics, The University of Chicago Medical Center
Xin He continued, “With our approach, we integrated genomics data generated from our center and integrated it with other databases to identify the underlying genetic interactions. This can lead us to genes that may be involved in this condition, which gives us a hint to the underlying biology.”
Although genetic factors are believed to play only a negligible role in the risk of preterm birth, the team was happy to observe such distinct results in their analysis.
“Preterm birth is so common, and some people experience it repeatedly. If you have a preterm birth, it doesn’t matter if it's genetic or not, you just don't want to experience one again. We can now use this information to better understand some of the genetic component and how it plays a role in the condition,” concluded Ober.
Upcoming studies will examine other cell types that may play a crucial role in preterm birth and pregnancy, for example, the immune cells residing at the maternal-fetal interface, and will analyze the effects of different environmental conditions on the expression of genes to develop the “roadmap” of genomic changes in endometrial cells.
Sakabe, N. J., et al. (2020) Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth. Science Advances. doi.org/10.1126/sciadv.abc8696.