Post-transcriptional control of stem and cancer cell fate. New roles for an old RNA modification.
(2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Recent advances in high-throughput sequencing technologies uncovered widespread RNA modifications on coding and non-coding RNAs collectively refer to as the epitranscriptome. However, we are only now starting to appreciate the impact of the epitranscriptome in regulating cell biology. Among more than 150 RNA modifications, I focused on pseudouridine (Ψ) the most abundant single-nucleoside RNA modification. Ψ is dynamically regulated upon stress and has the potential to rapidly modulate gene expression by controlling RNA biogenesis, stability, function and translation. Still, the biological role of Ψ remains poorly understood. In this thesis, I studied the contribution of Ψ in stem and cancer cell biology, with the ultimate goal of... (More)
- Recent advances in high-throughput sequencing technologies uncovered widespread RNA modifications on coding and non-coding RNAs collectively refer to as the epitranscriptome. However, we are only now starting to appreciate the impact of the epitranscriptome in regulating cell biology. Among more than 150 RNA modifications, I focused on pseudouridine (Ψ) the most abundant single-nucleoside RNA modification. Ψ is dynamically regulated upon stress and has the potential to rapidly modulate gene expression by controlling RNA biogenesis, stability, function and translation. Still, the biological role of Ψ remains poorly understood. In this thesis, I studied the contribution of Ψ in stem and cancer cell biology, with the ultimate goal of illuminating new molecular programs controlling development and malignant transformation.
Remarkably, in Paper I we uncovered an unanticipated role for the stem-cell-enriched Ψ synthase PUS7 in steering translation rate and dictating stem cell fate, through the modification of tRNA-derived fragments (tRF). In Paper II, we mechanistically dissected this new translational control pathway in stem cells and characterized the functional relevance of tRF dysregulation in hematological malignancies. In Paper III, we highlighted a critical interplay between the major oncogene MYC and PUS7, which converges on protein synthesis and steers MYC oncogenic program. In Paper IV, we characterized the impact of diet on small RNA composition in human sperm and identified a novel class of tRF selectively modulated upon diet intervention.
Collectively, my work unravels new post-transcriptional mechanisms that govern gene expression in space and time to direct cell fate and malignant transformation. Ultimately, results from these studies will extend our knowledge on the molecular programs regulating development and tumorigenesis, with potentially broad clinical implications. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/80247b2a-9152-49fc-87da-15c81ab9cf43
- author
- Guzzi, Nicola LU
- supervisor
-
- Cristian Bellodi LU
- Zaal Kokaia LU
- opponent
-
- professor Frye, Michaela, Deutsches Krebsforschungszentrum, Heidelberg
- organization
- publishing date
- 2020
- type
- Thesis
- publication status
- published
- subject
- keywords
- RNA modifications, pseudouridine, translational control, Stem cells, tRNA-derived fragments, MDS
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2020:110
- pages
- 78 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Belfragesalen, BMC D15, Klinikgatan 32 i Lund
- defense date
- 2020-09-24 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-7619-972-5
- language
- English
- LU publication?
- yes
- id
- 80247b2a-9152-49fc-87da-15c81ab9cf43
- date added to LUP
- 2020-08-19 16:43:22
- date last changed
- 2020-09-07 11:02:57
@phdthesis{80247b2a-9152-49fc-87da-15c81ab9cf43, abstract = {{Recent advances in high-throughput sequencing technologies uncovered widespread RNA modifications on coding and non-coding RNAs collectively refer to as the epitranscriptome. However, we are only now starting to appreciate the impact of the epitranscriptome in regulating cell biology. Among more than 150 RNA modifications, I focused on pseudouridine (Ψ) the most abundant single-nucleoside RNA modification. Ψ is dynamically regulated upon stress and has the potential to rapidly modulate gene expression by controlling RNA biogenesis, stability, function and translation. Still, the biological role of Ψ remains poorly understood. In this thesis, I studied the contribution of Ψ in stem and cancer cell biology, with the ultimate goal of illuminating new molecular programs controlling development and malignant transformation. <br/><br/>Remarkably, in Paper I we uncovered an unanticipated role for the stem-cell-enriched Ψ synthase PUS7 in steering translation rate and dictating stem cell fate, through the modification of tRNA-derived fragments (tRF). In Paper II, we mechanistically dissected this new translational control pathway in stem cells and characterized the functional relevance of tRF dysregulation in hematological malignancies. In Paper III, we highlighted a critical interplay between the major oncogene MYC and PUS7, which converges on protein synthesis and steers MYC oncogenic program. In Paper IV, we characterized the impact of diet on small RNA composition in human sperm and identified a novel class of tRF selectively modulated upon diet intervention. <br/><br/>Collectively, my work unravels new post-transcriptional mechanisms that govern gene expression in space and time to direct cell fate and malignant transformation. Ultimately, results from these studies will extend our knowledge on the molecular programs regulating development and tumorigenesis, with potentially broad clinical implications.}}, author = {{Guzzi, Nicola}}, isbn = {{978-91-7619-972-5}}, issn = {{1652-8220}}, keywords = {{RNA modifications; pseudouridine; translational control; Stem cells; tRNA-derived fragments; MDS}}, language = {{eng}}, number = {{2020:110}}, publisher = {{Lund University, Faculty of Medicine}}, school = {{Lund University}}, series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}}, title = {{Post-transcriptional control of stem and cancer cell fate. New roles for an old RNA modification.}}, year = {{2020}}, }