Endometriosis, which affects nearly one in 10 women of childbearing age, is characterized by the growth of uterine-like tissue outside organs, causing severe pelvic pain and infertility. Since endometriosis has no cure, treatment is limited to painkillers, hormonal contraceptives and agonists, and surgery. However, these can lead to menopausal symptoms and loss of bone density, and surgical recurrence rates are high.
Yingqun Huang of Yale University School of Medicine explores the epigenetic mechanisms of TET3 in metabolic diseases, cancer, and endometriosis.
Huang Yingqun
Despite its prevalence, endometriosis has been historically underfunded and underrecognized, leaving its mechanisms largely unknown. Yingqun Huang, a molecular biologist at Yale University School of Medicine, discusses the contribution of macrophages to the disease and how targeting specific populations of these immune cells can improve patient care.
What role do macrophages play in the pathophysiology of endometriosis?
For more than a decade, researchers have recognized the role of macrophages in lesion growth, blood vessel formation, and disease-related pain.1 Recently, my colleague Hugh Taylor and I analyzed an open-source single-cell RNA sequencing dataset collected from human endometriosis lesions and identified a specific population of pathogenic macrophages characterized by the protein TET3 Overexpression, we have previously shown that it affects gene regulation and is associated with various pathophysiological effects.2,3 We found in human and mouse in vitro models that increased expression of inflammatory cytokines leads to the formation of a new population of pathogenic TET3-overexpressing macrophages. This has genome-wide effects on macrophages, resulting in epigenetic modifications affecting cell survival and apoptotic pathways, making these macrophages dependent on TET3 relative to normal macrophages.
How do your findings address the challenges of treating endometriosis?
To target these pathogenic macrophages, we used a synthetic small molecule to trigger protein degradation of TET3. Because this compound relies on the coexpression of an enzyme that is also upregulated in these TET3-overexpressing macrophages, we used a dual cell-specific approach to target and kill this pathogenic cell population. We hope to develop this small molecule or its derivatives into a drug to treat endometriosis. Some clinical trials are investigating the effects of targeting these immune cells, but they focus on surface markers specific to non-pathogenic macrophages. We believe our small molecules specifically target disease-associated macrophages.
Abbreviation: TET3 (tet methylcytosine dioxygenase 3).
This interview has been edited for length and clarity.
