Description
- Abstract:
- Abstract of “Regulating Transcription, Epigenetics, and Stemness During Embryonic Male Germ Cell Development” by Myles A. Bartholomew, Ph.D., Brown University, May 2026. Male infertility is on the rise, with sperm counts declining by over 50% in the past 40 years. By understanding the complex transcriptional and epigenetic regulation involved in the development of spermatogonial stem cells (SSCs) from prospermatogonia (ProSpg), we may be able to treat a subset of idiopathic male infertility. The field's current understanding suggests that early postnatal SSCs arise from ProSpg shortly after birth in the mouse. However, the mechanism by which this definitive stem cell population first emerges during ProSpg development remains elusive. Studies using germ cell transplants as early as e18.5 have shown success in rescuing spermatogenesis in mature germ cell-ablated mice. Therefore, we propose that SSC programs and progenitors might be regulated earlier than previously described. Our integration of human and mouse scRNA-seq data reveals that TAF4b is co-expressed with markers of undifferentiated spermatogonia and SSCs throughout development, and disruption of TAF4b in the mouse disrupts long-term spermatogenesis. This is substantiated by work showing that in multiple human populations, individuals with TAF4B mutations are azoospermic. Using multi-omics approaches in TAF4b-deficient mice, we have discovered that TAF4b regulates ProSpg quiescence by controlling gene networks involved in cell-cycle regulation and chromatin modification. Furthermore, dysregulation of chromatin and epigenetic regulators during late embryonic development is associated with aberrant expression of retrotransposable elements and significantly increased prospermatogonial apoptosis. Here, using a TAF4b-GFP-expressing mouse model and biophysical cytometry, I have identified the timely emergence of a novel subset of germ cells characterized by low intracellular complexity (LIC). This unique developmental bifurcation is largely dependent on TAF4b, and we have confirmed its emergence in multiple germ cell reporter lines. Finally, we present evidence that the same E18.5 TAF4b-GFP-expressing cells harbor stem cell activity as measured by germ cell transplants. Future characterization of the novel LIC population and why it is lost in Taf4b Def male mice may offer new molecular insights into germline stem cell development and fate determination both in rodents and men. Here, we present our latest findings on dissecting a critical TAF4b-dependent gene regulatory network required for proper male embryonic germline development and adult long-term spermatogenesis.
- Notes:
- Thesis (Ph. D.)--Brown University, 2026
Citation
Bartholomew, Myles Austin,
"Regulating Transcription, Epigenetics, and Stemness During Embryonic Male Germ Cell Development"
(2026).
Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:en2m3vuw/
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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations
Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department....