Dissecting the mechanisms of translational regulation in Drosophila germ stem cells

Lead Research Organisation: University of Leeds
Department Name: Inst of Molecular & Cellular Biology

Abstract

Background
STAR (signal transduction and activation of RNA) proteins are KH-domaincontaining, RNA-binding proteins whose activity is regulated in response to signals and regulate RNA processes. One family member is Drosophila HOW, which is expressed in the brain, testes and muscles. Mutants exhibit slow heart rates, heart defects and male sterility. Orthologs have been shown to regulate mRNA translation eg. p53 mRNA in C.elegans. HOW is required for germ stem cell maintanence in Drosophila testes and binds to RNAs that regulate differentiation in testes.
Objectives
1)Identify mRNAs translationally regulated by HOW in testes
2)Characterise molecular mechanism of translational regulation by HOW
3)Understand role of HOW regulated translation events in germ cells

Novelty
Transciptome-wide studies of translation have only been possible in the last few years, with most determining regions of translation and translational efficiencies. Combining ribosome profiling with structural analysis and Drosophila genetics is an innovative strategy, to dissect the molecular mechanisms of translational control by a specific protein.

Timeliness
The advent of ribosome profiling recently allowed global assessments of translational regulation. Improvements to the method, including ours (Aspden eLife 2014) now allow translational regulation by specific proteins to be measured. The dogma has been that the majority of gene expression regulation occurs at transcription but recent work has revealed mRNA translation is also a key point of regulation, eg binding of proteins to mRNAs alters the ability of ribosomes to initiate translation. Structural studies of STAR-proteins are currently at the point (including Edwards group), where mechanistic insight into how binding affects RNA activity can be achieved.

Experimental Approach
-Next Generation Sequencing to study translational control (ribosome profiling)
-Biochemical structural methods to understand how RNA-binding occurs and how this affects the ribosome (X-ray crystallography)
-Drosophila genetic analysis to assess how molecular interactions affect germ stem cell biology and fly fertility.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011151/1 30/09/2015 29/09/2023
1775122 Studentship BB/M011151/1 30/09/2016 30/03/2021 Michaela Agapiou
 
Description Bursary for Drosophila Genetics and Genomics 2018 Course
Amount £325 (GBP)
Organisation Wellcome Genome Campus 
Sector Private
Country United Kingdom
Start 06/2018 
End 08/2018
 
Description Junior Scientist Conference Grant
Amount £750 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2020 
End 05/2020
 
Description Junior Scientist Travel Grant
Amount £595 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 09/2017
 
Description RNA Society Travel Fellowship
Amount $625 (USD)
Organisation RNA Society 
Sector Charity/Non Profit
Country United States
Start 04/2020 
End 05/2020
 
Description Sponsored Seminar Series Grant
Amount £500 (GBP)
Organisation Biochemical Society 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2019 
End 08/2020
 
Description Student Member Bursary
Amount £191 (GBP)
Organisation Biochemical Society 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2018 
End 07/2018
 
Description Training Grant
Amount £450 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2018 
End 08/2018
 
Description Story told for Story Collider 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact During my PIPS placement I worked with The Story Collider. Part of this was telling a story on stage in New York that was true, personal and related to science. These stories aim to humanise science and scientists to the general public and also to share that science is for everyone. I shared a story of an unpleasant lab experience that taught me how important having a good supervisor and team are, which directly led to me choosing my current PhD project. This story was told to an audience of around 100 people and was recorded, with the potential for it to be shared in the future on The Story Collider's podcast which has over 200,000 weekly listeners.
Year(s) Of Engagement Activity 2019
URL https://www.storycollider.org/shows/2019/4/1/new-york-ny-fool-me-once