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Post-transcriptional control of stem and cancer cell fate. New roles for an old RNA modification.

Guzzi, Nicola LU (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)
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author
supervisor
opponent
  • professor Frye, Michaela, Deutsches Krebsforschungszentrum, Heidelberg
organization
publishing date
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}},
}