Functions of the ERK5 signalling pathway in Pluripotent Stem Cells
Lead Research Organisation:
University of Dundee
Department Name: School of Life Sciences
Abstract
Pluripotent Embryonic Stem Cells (ESCs) have the capacity to self-renew and differentiate into all specialized cell types in the adult body. ESC decision-making is tightly controlled by cellular signalling networks, which our lab seeks to unravel and exploit to elaborate novel ESC-based cell replacement strategies (Fernandez-Alonso et al, 2017). In a recent small molecule kinase inhibitor screen, we uncovered a critical function for the ERK5 signalling pathway in controlling ESC pluripotency. Using inhibitor engineering and CRISPR/Cas9 genome editing, we find, excitingly, that ERK5 modulates transition between "naïve" and "primed" pluripotent ESC states (Williams et al, 2016). We are now applying cutting-edge quantitative systems biology technologies to unravel molecular functions of ERK5 in ESCs. As ERK5 uniquely contains a kinase domain and a putative transcriptional domain, a key aim is to gene whose expression is regulated by ERK5. To this end, we will define the role of ERK5 in regulating ESC gene expression and proteome dynamics using RNA-SEQ transcriptomics and total proteomic profiling mass-spectrometry. This uncovers a new function for the ERK5 signalling pathway in regulating expression of early embryonic genes associated with reprogramming to naïve pluripotency and attaining totipotency, an embryonic state that is developmentally unrestricted. Therefore, we to identify molecular mechanisms that activate ERK5 signalling in ESCs, and exploit this information to reprogram somatic cells to naïve pluripotency and potentially totipotency. Ultimately, this knowledge will provide new avenues towards reprogramming cells more efficiently and towards totipotency.
Key Words: Embryonic Stem Cell, Regenerative Medicine, Signal Transduction, Protein Kinase
Quantitative Skills: Quantitative Mass-Spectrometry, Transcriptomics
Whole Organism Physiology: Systems Biology, Stem Cells
Questions:
1. Explain interdisciplinary interface: This project interfaces quantitative analysis with systems biology and whole organism physiology by employing quantitative mass-spectrometry and transcriptomic profiling to address systems biology question in stem cells
2. Does project require significant amount of quantitative skills? YES
3. Does project require significant amount of whole organism physiology skills? YES
Key Words: Embryonic Stem Cell, Regenerative Medicine, Signal Transduction, Protein Kinase
Quantitative Skills: Quantitative Mass-Spectrometry, Transcriptomics
Whole Organism Physiology: Systems Biology, Stem Cells
Questions:
1. Explain interdisciplinary interface: This project interfaces quantitative analysis with systems biology and whole organism physiology by employing quantitative mass-spectrometry and transcriptomic profiling to address systems biology question in stem cells
2. Does project require significant amount of quantitative skills? YES
3. Does project require significant amount of whole organism physiology skills? YES
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/R502297/1 | 01/09/2017 | 28/02/2022 | |||
| 2221349 | Studentship | MR/R502297/1 | 01/09/2017 | 31/08/2021 |
| Description | Nanog phosphosite identification |
| Organisation | University of Edinburgh |
| Department | MRC Centre for Regenerative Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I have identified phosphosites for this protein through mass spectrometry analysis. |
| Collaborator Contribution | They identified kinases which phosphorylate this protein. |
| Impact | No outcomes as yet, although one paper is in preparation. |
| Start Year | 2019 |
| Description | UHRF1 phosphosite identification |
| Organisation | Babraham Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I have identified phosphosites for this protein through mass spectrometry analysis |
| Collaborator Contribution | They have identified kinases that phosphorylate this protein |
| Impact | No outcomes yet, although one paper in preparation. |
| Start Year | 2019 |
| Description | Animating Science workshop |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Researchers were taught how to make short stop motion animated films to depict their scientific concept. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Art Science and Visual Thinking Tutor |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Undergraduate students |
| Results and Impact | I presented my work to undergraduate art students to provide an opportunity for them to collaborate with me on a visual interpretation of my topic. Several students approached me afterwards, which led to an ongoing working group with one of them. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Bake Your Science |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | 3 researchers spent a day baking science-related food, then posted pictures on social media explaining the scientific concept and nature of the bake. This led to lots of interest, mainly from postgraduate students and principle investigators, on social media, and some responses from other scientists "baking their science". |
| Year(s) Of Engagement Activity | 2018 |
| Description | Dundee University Open Day |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Undergraduate students |
| Results and Impact | I had a stall at the University Undergraduate Open Day to publicise the quality of research at the University. Several undergraduates were interested in my research topic and which professors' lectures would be particularly interesting. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Dundee University Street Food |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Life Science labs collaborated with local food/drink producers to find a link between the scientific research and the food product. Member of the general public were then able to ask questions and spark discussions about the science and sample the food, which led to a better understanding and appreciation of the work done at the school of life science. My collaboration was with Sacred Grounds coffee, showing ESCs differentiating into cardiomyocytes, which are progenitors of heart muscle, which beats faster if a person drinks caffeinated drinks such as coffee. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Engagement with prospective students |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | I met with prospective biochemistry undergraduates and their families to discuss what biochemistry is, what the career options are, and the nature of the course at Oxford University (where I studied for my undergraduate degree). This influenced some decisions regarding which course to apply for and at which university. |
| Year(s) Of Engagement Activity | 2019 |
| Description | MRC Festival |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Around 50 pupils attended for a school visit to the institute, and were exposed to talks from scientists, interactive activities, and an opportunity for small group Q&A sessions with researchers. This increased interest in subject areas and initiated conversations about career options in science. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Max Perutz writing competition |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | I wrote an article explaining why basic stem cell biology research is important for a non-scientific audience for submission to the Max Perutz writing competition. Although I was not shortlisted, I issued the article to friends and family to be distributed, so that more people could understand what it is that I work on. I received reports of interest in the subject area, leading to discussions about my work, including questions of ethics surrounding stem cell research. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Science baking |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | I baked a cake depicting a colleague's research interests, and posted pictures and an explanation on social media. This sparked interest in their topic, largely from non-scientists. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Seminar at St Andrews University |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Undergraduate students |
| Results and Impact | 20 undergraduate students came to my seminar in their University Biological Society's seminar series. The intended purpose was to introduce the concept of studying biochemical signalling, and why this is important. Most audience members engaged in discussion about the work, and a politics student who attended chose to become a member of the society after hearing my talk. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Soapbox Science Edinburgh |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | 12 women in STEM gave 1 hour talks to members of the general public who passed by the event. The average dwell time at each speaker was 7 minutes (compared to an average of 2.5 minutes for Soapbox Science in other cities). 700 people engaged with the speakers over the course of the 4 hour event. Members of the public asked questions about the research, the future applications, and career opportunities for women in science. One particular discussion about the ethics of work on stem cells led to a number of audience members changing their mind to support this work rather than oppose it. Several younger girls voiced an enthusiasm for going into a scientific career. |
| Year(s) Of Engagement Activity | 2018 |
| URL | http://soapboxscience.org/soapbox-science-2018-edinburgh/ |
| Description | The Great MRC PPU Bake Off |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Researchers from the MRC PPU competed in a baking competition to raise money for charitable causes. I won 3rd place with "anatomical heart cakes" which sparked interest and conversation on social media afterwards. |
| Year(s) Of Engagement Activity | 2019 |