ABOVE: Endometrial stromal fibroblasts, one of the endometrial cell types which expresses HAND2


The paper
M. Marinić et al., “Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length,” eLife, doi:10:e61257, 2021. 

Scientists don’t fully understand the molecular mechanisms that conclude human pregnancies. Simply put: “We don’t know how women go [into] labor,” says Mirna Marinić, a developmental biologist at the University of Chicago, adding that pregnancy in animal models is often too different from that of humans to be very informative.

Still, understanding how differences between animal and human pregnancies arise could provide novel insights into how labor is triggered. Marinić and her team compared gene expression profiles in the endometrial tissue that forms the maternal-fetal barrier across 27 species—including 18 live-birthing mammals, the egg-laying platypus, and eight other egg-laying animals—to look for shifts in gene expression associated with the evolution of different reproductive strategies. 

The analyses revealed 149 genes that had evolved to be expressed in the endometrial tissue of placental mammals, and of those, a transcription factor called heart- and neural crest derivatives-expressed protein 2 (HAND2) stood out. The gene is known to play a role in prepping the uterine lining for implantation and suppressing estrogen signaling; reexamining published data, the team found that HAND2 expression decreases throughout human gestation. The researchers then knocked out HAND2 in human endometrial cells and identified changes in the expression patterns of genes associated with premature birth and protecting the fetus from the mother’s immune system, strongly pointing to a role for HAND2 in initiating labor. 

“This is really exciting, because it’s leading us to genes that might be important,” says Rachel Freathy, a genetic epidemiologist at the University of Exeter who was not involved in the study. Freathy identifies genomic regions involved in preterm birth, and says she was excited by the researchers’ experimental approach. “It was a great bridge from the kind of work that we do that brings up associations to actually getting to the mechanisms in the right tissues.”