Using mouse genomic data, genome editing, and bioinformatics, a team led by NIEHS scientists determined that a protein in humans and mice called SOX17 may be critical to a woman’s ability to become pregnant.

The researchers found that the transcription factor SOX17 works with the progesterone hormone receptor in female mice to regulate the ability of the uterus to support embryo implantation. The scientists hope they can use the information to eventually turn stem cells into healthy uterine lining cells, which would help some women with infertility or uterine disease. The study was published online Oct. 24 in Nature Communications.

Uterine specific

In addition to his duties as lab chief, DeMayo heads the NIEHS Pregnancy and Female Reproduction Group. (Photo courtesy of Steve McCaw)

Corresponding author, Francesco DeMayo, Ph.D., head of the NIEHS Reproductive and Developmental Biology Laboratory, said that SOX17 has two important functions in the mouse — regulating the development of the uterus and regulating the genes that support embryo implantation. DeMayo and his group examined mouse RNA to determine where SOX17 binds in the genome. They identified a site near a gene involved in embryonic development called Indian hedgehog (Ihh).

'When we used CRISPR-Cas9 technology to delete the SOX17 binding site, we lost Indian hedgehog expression, specifically in the uterus,' explained DeMayo. 'While hedgehog is expressed in other tissues, the observation told us that the SOX17 binding site is specific to the uterus.'

Removing the SOX17 binding site or the entire SOX17 gene alters the communication between the epithelial cells that line the inside of the uterus and the stroma, which is uterine supportive tissue made of connective tissue and blood vessels. As a result, the uterus does not form properly and is unable to support pregnancy. When SOX17 is present, DeMayo said it works with the progesterone receptor to control the ability of the uterus to receive an embryo.

Xiaoqiu Wang, Ph.D., an NIEHS Intramural Research Training Award fellow, served as lead author for the journal article. (Photo courtesy of Steve McCaw)

SOX17 impacts women’s health

DeMayo’s group found that mouse SOX17 uses Ihh to communicate with and regulate uterine genes. Because humans also have SOX17 and Ihh, he said that infertility in some women may be due to a dysfunctional SOX17 gene.

Co-author Xiaoqiu Wang, Ph.D., an NIEHS Intramural Research Training Award fellow, said the team found that SOX17 is altered in endometriosis, a painful disorder that develops when tissue that normally lines the uterus appears outside of the uterus.

Therapeutic potential

In the future, DeMayo said that a couple having infertility issues could seek help from a physician who might be able to determine if a woman’s SOX17 gene is altered. Also, in diseases in which patients do not respond well to progesterone therapy — such as endometriosis, endometrial cancer, and some infertility cases — examining how SOX17 regulates uterine function may help diagnose and eventually aid in the development of specific therapies.

'This paper presents a seminal work that explores the signaling network of the pregnancy hormone progesterone,' Wu said. (Photo courtesy of Steve McCaw)

Co-author and NIEHS Staff Scientist Steve Wu, Ph.D., said that in addition to discovering that SOX17 and progesterone receptor bind at the Ihh site, DeMayo’s group identified several other transcription factors that bind there, too.

Wu and his colleagues wonder if they can use different combinations of these transcription factors to make an artificial uterus. Such a platform would allow screening of environmental toxins or testing of drugs that change the thickness of uterine linings. Thin linings prevent proper embryo implantation.

'The identification of a combination of proteins required for pregnancy and their regulation of gene expression opens up a new research front in the study of uterine functions,' Wu said.

Citation: Wang X, Li X, Wang T, Wu S-P, Jeong J-W, Kim TH, Young SL, Lessey BA, Lanz RB, Lydon JP, DeMayo FJ. 2018. SOX17 regulates uterine epithelial-stromal cross-talk acting via a distal enhancer upstream of Ihh. Nat Commun 9(1):4421.