Seminar: Post-transcriptional regulation of RNA stability: a central element during hematopoietic development and disease
| Date/Time: | Monday, 18 Mar 2024 from 1:00 pm to 1:50 pm |
|---|---|
| Location: | 1414 Molecular Biology |
| Cost: | Free |
| Contact: | Danise Jones |
| Phone: | 515-294-2687 |
| Channel: | Research |
| Categories: | Lectures |
| Actions: | Download iCal/vCal | Email Reminder |
Mutations in telomerase cause bone marrow failure in patients suffering with dyskeratosis congenita and associated telomere biology disorders. While mutations in these patients are found in different components of the telomerase complex, mutations in genes that regulate the processing and function of the RNA component of telomerase, TERC, are the most prevalent, and associated with severe phenotypes. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular pathways that control TERC biogenesis in hematopoietic cells remain largely unknown. Progress in the field has been hampered by species and even cell-type specific differences in telomerase that limit our understanding of the molecular mechanisms leading to the disproportionate role of TERC in hematopoietic failure when compared to other components of telomerase. A better understanding of the molecular regulation of TERC processing in hematopoietic cells is essential for development of alternative therapeutics for patients, which remain without a cure. To address this issue, we generated a novel panel of human embryonic stem cells (hESCs) harboring mutations in different genes involved in the molecular biogenesis of TERC. From these hESCs we derived hematopoietic progenitors in vitro, following protocols that recapitulate blood development in vivo. Utilizing this platform, we identified novel regulators of TERC processing, both at its 3?- and 5?- ends, that directly modulate its cellular trafficking and decay in hematopoietic cells. We showed that this pathway of TERC decay is highly active in cells harboring clinically relevant mutations in telomerase. Indeed, inhibition of these new TERC degradation pathways restored telomerase activity in telomerase mutant stem cells back to wild-type levels, followed by efficient, sustained, maintenance of telomere length. Notably, we achieved these results not only with genetic silencing, but also with chemical inhibitors of these same pathways. As outcomes for patients with reduced TERC levels are poor and little is known about the pathways regulating TERC processing in erythroid, myeloid, and lymphoid cells, our data opens new pathways to be explored for clinical management of bone marrow failure patients with mutant telomerase.