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Uncovering the role of PUS10 and RNA pseudouridylation in somatic cell reprogramming and cell fate determination

Finan, Hannah (2022) MOBN02 20212
Degree Projects in Molecular Biology
Popular Abstract
Uncovering the role of PUS10 and RNA pseudouridylation in somatic cell reprogramming and cell fate determination

RNA modifications are emerging as dynamic regulators of gene expression programmes in development and disease. The isomerisation of uridine to pseudouridine (Ψ) is the most widespread modification in living organisms. Previously thought to be a static RNA mark, Ψ is currently known to be dynamically regulated upon various stress conditions and has been critically involved in governing protein synthesis and stem cell differentiation. Ψ is catalysed by a family of enzymes called pseudouridine synthases (PUS) or “Ψ writers” such as PUS10 with poorly defined roles in humans.

As previous results from our lab highlight a... (More)
Uncovering the role of PUS10 and RNA pseudouridylation in somatic cell reprogramming and cell fate determination

RNA modifications are emerging as dynamic regulators of gene expression programmes in development and disease. The isomerisation of uridine to pseudouridine (Ψ) is the most widespread modification in living organisms. Previously thought to be a static RNA mark, Ψ is currently known to be dynamically regulated upon various stress conditions and has been critically involved in governing protein synthesis and stem cell differentiation. Ψ is catalysed by a family of enzymes called pseudouridine synthases (PUS) or “Ψ writers” such as PUS10 with poorly defined roles in humans.

As previous results from our lab highlight a function for PUS7-mediated Ψ in regulating stem cell differentiation, the question arose if PUS-mediated Ψ also affects reverse processes like reprogramming. Differentiated, somatic cells can be “reprogrammed” to induced pluripotent stem cells (iPSCs) upon forced expression of Sox2, c-Myc, Oct4, and Klf4, known as the Yamanaka factors. Although somatic cell reprogramming has been transformative in regenerative medicine, it remains highly inefficient. Strikingly, we showed that the multi-substrate Ψ “writer”, PUS10, significantly enhances the reprogramming efficiency through potential effects on cell metabolism and genome integrity.

Here, we are investigating the underlying mechanisms by which PUS10 contributes to somatic reprogramming and germ layer differentiation. Unpublished data from our group suggest that PUS10 may have a dichotomous role in the regulation of protein synthesis and the cellular stress response to DNA damage in primary murine and human fibroblasts. Additionally, we find that loss of PUS10 perturbs the DNA damage response signalling pathway and this likely involves modulation of p53, a central tumour suppressor and negative regulator of somatic reprogramming. Whether PUS10-mediated pseudouridylation impacts cellular reprogramming through p53 signalling remains a key unanswered question.

The overarching aim of my master’s project is to determine the con¬tribution of PUS10-mediated Ψ towards somatic reprogramming and cell fate determination (Figure 1).

This project reveals that reprogrammed cells lacking PUS10 display cell proliferation and global de novo protein synthesis alterations. p53 target genes were also found to be upregulated but have not been validated. Together, our data indicates that reprogramming regulation through changes in translation or DDR could be possible. Our results underscore the diverse role of Ψ in cell fate determination and reprogramming.

Master’s Degree Project in Molecular Biology 45 credits 2022
Department of Biology, Lund University

Advisor: Cristian Bellodi
RNA & Stem Cell Biology laboratory, Div Mol Hematology, Dept. Laboratory Medicine, Lund University (Less)
Please use this url to cite or link to this publication:
author
Finan, Hannah
supervisor
organization
course
MOBN02 20212
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9082095
date added to LUP
2022-05-31 12:36:33
date last changed
2022-05-31 12:36:33
@misc{9082095,
  author       = {{Finan, Hannah}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Uncovering the role of PUS10 and RNA pseudouridylation in somatic cell reprogramming and cell fate determination}},
  year         = {{2022}},
}