In a joint effort, scientists from the Indian Institute of Science (IISc), ICMR – National Institute for Research in Reproductive and Child Health (NIRRCH), Mumbai and Banaras Hindu University (BHU), Varanasi, have identified the basic genetic switch that enables pregnancy to begin.
According to IISc, to start a pregnancy, the embryo must first attach and embed itself in the lining of the uterus – a process called implantation.
“Implantation failure is one of the main causes of infertility and early pregnancy loss and IVF failure. However, the molecular mechanisms that allow the uterus to become receptive remain poorly understood,” said IISc.
Now, scientists have identified a fundamental genetic switch that allows the uterine lining to acquire a state that supports embryo implantation.
A study published in Cell Death Discovery shows that two key genes, HOXA10 and TWIST2, work in opposition to regulate this transition.
Under normal conditions, HOXA10 keeps the endometrium stable and compact. At the time and place where the embryo is about to begin implantation, HOXA10 activity declines, allowing TWIST2 to be activated. TWIST2 makes the cells a little more mobile and flexible, allowing the embryo to settle on its own.
At the molecular level, HOXA10 controls over 1,200 genes that maintain the epithelial (closed) state of the endometrium. When HOXA10 levels drop, this control is released, leading to activation of TWIST2 and the onset of hybrid epithelial-mesenchymal transition (hybrid EMT)—a temporary and partial shift that allows controlled uterine cell movement without full transformation.
Mathematical modeling
To understand the regulatory logic of this process, IISc researchers used mathematical and computational modeling to simulate the interplay between HOXA10 and TWIST2. Their models showed that the system behaves as a bistable genetic circuit, capable of switching between epithelial and mesenchymal states in a stable, reversible manner.
“This kind of hybrid EMT state is an elegant solution that nature uses to balance stability and flexibility,” said Mohit Kumar Jolly, associate professor in the Department of Bioengineering, IISc, who led the modeling work.
Biological studies led by Deepak Modi, professor and scientist at ICMR–NIRRCH, have experimentally confirmed this mechanism in mice, hamsters, monkeys and human cells. When TWIST2 activation was blocked, the uterine lining did not remodel and embryos could not implant, preventing pregnancy.
“This work reveals a fine-tuned molecular program that prepares the uterus for embryo implantation. It helps us understand why implantation sometimes fails even when the embryos are healthy,” said Prof. Modi.
Wider implications
“Beyond reproductive health, these findings may have wider implications for understanding tissue remodeling in wound healing, fibrosis and cancer, where similar gene networks operate,” Professor Jolly said.
Published – 20 Nov 2025 19:23 IST
