Matthew Brook
Principal Investigator (UoE/CVS) and PhD Programme Director/Lecturer (UoE/ZJE)
Address
- Street
-
Centre for Cardiovascular Science
Queen's Medical Research Institute
University of Edinburgh
Edinburgh Bioquarter
47 Little France Crescent
Edinburgh - City
- Post code
- EH16 4TJ
Qualifications
BSc Biochemistry: University of Essex
MPhil Biochemistry: University of Manchester (Regulation of proliferation and differentiation of the rat intestinal epithelium)
PhD Molecular Biochemistry: Imperial College London (Regulation of TNF-alpha gene expression by p38 mitogen-activated protein kinase)
Responsibilities & affiliations
Biochemical Society - Member of Research Area I (Genes) panel & Local Ambassador for University of Edinburgh
Associate Editor - Frontiers in Molecular Biosciences (RNA Networks and Biology)
Review Editor - Frontiers in Endocrinology (Systems Endocrinology)
FEBS Letters Advisory Board
Centre for Cardiovascular Sciences - Research Integrity Team
Undergraduate teaching
Assistant Professor at Zhejiang University-University of Edinburgh (ZJE) Institute, lecturing on the Biomedical Sciences Joint Honours degree program.
2020- 2024 - Joint Coordinator of Years 3&4 for the Integrated Biomedical Sciences (BMS) and Biomedical Bioinformatics (BMI) degree programmes.
2019 - 2024 - Course Organiser for "Integrated Biomedical Science 4 (IBMS4)" and "Future Perspectives" 4th year courses.
Postgraduate teaching
UoE PhD Programme Director (ZJE: UoE single award and UoE/ZJU Dual Award)
Open to PhD supervision enquiries?
Yes
Areas of interest for supervision
Project 1: Mechanistic characterisation of regulation of PABPC1 by post-translational modification in response to nutrient availability
Applications are invited from outstanding students (self-funded or Scholarship/fellowship holders) wishing to pursue PhD studies.
Candidates must meet University of Edinburgh/Centre for Cardiovascular Science PhD requirements (including English language proficiency)
How to apply
To apply, email matt.brook@ed.ac.uk and include:
- your CV (including details of minimum of 2 supporting referees)
- a 1-page statement of why you wish to pursue a PhD and why you wish to pursue this project.
- A statement detailing your plan to fund the studentship (e.g. self-funding, organisation providing fellowship (and whether it has been awarded or being applied for
Project description
PABPC1 is central to normal regulation of mRNA translation and decay. By binding mRNA poly(A) tails and interacting with a suite of partner proteins, PABPC1 confers disparate regulatory outcomes to mRNAs. However, despite many protein partners binding at overlapping or shared sites, the regulation of PABPC1-partner interactions is very poorly understood.
We have previously demonstrated PABPC1 to be extensively post-translational modified (PTM); ranging from S/T/Y phosphorylation and R methylation to more unusual K acetylation/methylation switches and Q/D methylation. To date, the functional relevance, regulatory mechanism, and upstream signalling pathways of almost all these PTMs remains unknown.
However, we have determined that PABPC1 is subject to regulation in response to nutrient status, cell cycle stage, and viral infection, indicating that full understanding of PABPC1 PTM-mediated regulation may uncover novel pathways of gene expression regulation.
To reveal novel systems of post-transcriptional regulation of gene expression that underpin nutrient responsiveness and metabolic homeostasis, we will quantitatively determine PABPC1 PTM responses to nutrient availability and perform mechanistic studies of PTM effects on (for e.g.) protein partner binding, mRNA target selection/mRNA binding, and utilisation/fate of target mRNAs (e.g. translation, poly(A) tail status, decay), and we will delineate upstream signalling pathways of nutrient-responsive PTMs.
Aim 1: PTM-omics analysis of PABPC1 to fully characterise its post-translational regulation in response to nutrient availability. Aim 2: Mechanistic characterisation of the effects of nutrient-responsive PTMs on PABPC1 protein partner and/or mRNA interactions. Aim 3: Mapping of upstream regulatory signalling pathways that modulate nutrient-responsive PABPC1 PTMs to affect metabolic gene expression.
Approaches used in project
The student will receive training in cutting-edge methods to study: The identification of PABPC1 PTMs and regulated outcomes, interactions and upstream pathways will require combinations of proteomics/PTMomics, biophysical and structural studies (e.g. SPR, crystallography/NMR), transcriptomics, post-transcriptional regulation of gene expression studies (e.g. RNA-binding protein function, RNA target identification) and in vitro cell metabolism methods (e.g. cellular respiration).
The supervisory team encompasses all the required expertise and will fully support method training and deployment. In addition, training will be provided in bioinformatics approaches to data handling/analysis, as required
Relevant references for project background
1. Brook M, McCracken L, Reddington JP, Lu ZL, Morrice NA, Gray NK. (2012) Biochem J. 441(3):803-12. The multifunctional poly(A)-binding protein (PABP) 1 is subject to extensive dynamic post-translational modification, which molecular modelling suggests plays an important role in co-ordinating its activities. [PMID: 22004688]
2. Friend K, Brook M, Bezirci FB, Sheets MD, Gray NK, Seli E. (2012) Embryonic poly(A)-binding protein (ePAB) phosphorylation is required for Xenopus oocyte maturation. Biochem J. 445(1):93-100. [PMID: 22497250]
3. Shan P, Fan G, Sun L, Liu J, Wang W, Hu C, Zhang X, Zhai Q, Song X, Cao L, Cui Y, Zhang S, Wang C. (2017) SIRT1 Functions as a Negative Regulator of Eukaryotic Poly(A)RNA Transport. Curr Biol. 27(15):2271-2284.e5. [PMID: 28756945]
4. Passmore LA, Coller J. (2022) Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression. Nat Rev Mol Cell Biol. 23(2):93-106. [PMID: 34594027]
Current PhD students supervised
Primary Supervisor:
Nadia Patel (4-year Biomedical Science PhD student - Co-Supervised by Prof. Nicola Gray (Centre for Reproductive Health, UoE), Prof. Rob Semple (Centre for Cardiovascular Science, UoE) and Dr. Tuomas Kilpeläinen (NNF Centre for Basic Metabolic Research, University of Copenhagen)
Natasha Arzoo (PhD Student - Co-Supervised by Dr. Robert Young (Usher Institute, UoE) [Pakistan HEC Scholarship]
Co-Supervisor:
Honglin Yu (PhD Student ZJE Institute, China - with Dr. Di Chen (ZJE Institute)
Qizhe Shao (PhD Student ZJE Institute, China - with Dr. Di Chen (ZJE Institute)
Junping Shi (PhD Student ZJE Institute, China - with Dr. Robert Young (Usher Institute, UoE) and Dr. Xianghua Li (Sanger Institute, Cambridge)
Hongling Liu (PhD Student - with Prof. Nik Morton (PI) (UoE/Nottingham-Trent University) and Prof. Kei Sakamoto (CBMR, Uni. Copenhagen)
Triin Ounapuu (PhD Student - with Prof. Nicola Gray (PI))
Past PhD students supervised
Primary Supervisor:
Rupashri Balaraman (MSc)
Yuhan Qin (BSc)
Shiyang He (MSc)
Ana Ingels (MSc)
Saidiburkhaniddin Adikhanov (MSc)
Lara Scheer (MSc)
Yan Xu (MSc)
Yanjing Zhao (MSc)
Co-Supervised with Prof. Nicola Gray:
Mathias Lorbeer (PhD)
Hristina Gyurova (PhD)
Tajekesa Blee (PhD)
Lenka Hrabalkova (PhD)
Jessica Scanlon (PhD)
Sarah Howard (MSc)
Maria Casacao (MSc)
Huanting Chi (MSc)
Emily Walshe (MSc)
Melina Michael (BSc)
Rachael Smith (BSc)
Research summary
I am fascinated by the molecular 'circuitry' that underpins a cell's ability to produce all the proteins it requires for its viability and correct function. Without this 'circuitry' there would be nothing to ensure that proteins are made at the right time, in the correct location and in the correct amounts, therefore it is essential for life. However, the combinations of intracellular signalling and responsive gene expression that comprise the molecular 'circuits' do not always work perfectly, e.g. due to gene mutations and/or environmental influences (such as diet) and this can lead to morbidity/disease (e.g. cancer, metabolic and cardiovascular disease, neurodegenerative disease, reproductive disorders etc.....).
It is therefore crucial that we first determine the normal cellular mechanisms that control protein synthesis. By identifying the mechanistically-required protein and RNA factors and, critically, by delineating the way in which signals from outside and inside the cell are relayed to these factors, we build a platform from which to begin understanding how protein synthesis becomes dysregulated in disease/morbidity.
Unfortunately, vast proportions of the molecular circuitry of normal metabolic and cardiovascular health remain to be uncovered and we are therefore unable to fully understand the mechanisms by which metabolic and cardiovascular diseases arise and/or progress. We aim to change this.
Current research interests
In the lab, we take complementary approaches to deciphering post-transcriptional regulation: 1) We take a targeted approach and simultaneously work to understand i) how specific RNA-binding proteins (RBPs) function to coordinate gene expression, ii) how specific RNA-binding protein functions are regulated by post-translational modifications (such as phosphorylation, acetylation and methylation) in response to specific cellular signals and iii) what signalling pathways and effector enzymes carry out these specific post-translational modifications. 2) We take an agnostic approach and aim to elucidate the post-transcriptional molecular circuitry of disease/morbidity by identifying expression and/or post-translational modification changes in the total cellular RBP-ome and changes in the RNA-binding status of all expressed RBPs (general and substrate-specific). These are multidisciplinary investigations that require both routine and cutting-edge methodologies and expertise (e.g. site-specific post-translational modification of recombinant proteins using codon extension/unnatural amino acids, surface plasmon resonance, X-ray crystallography, quantitative mass spectrometry, RBP interactome capture) and which range from in vitro methods using purified components through to in vivo physiology……and all in between. 3) Working with key collaborators at University of Edinburgh and The Centre for Basic Metabolic Research (CBMR), University of Copenhagen, Denmark, we employ population genetics approaches combined with genome-wide gene expression dataset analyses to identify human genetic variants that directly or indirectly affect post-transcriptional regulation of gene regulatory networks underpinning cardiometabolic health and disease.Past research interests
My previous projects have primarily centred around specific RNA-binding proteins such a Tristetraprolin (TTP) or members of the poly(A)-binding protein (PABP) family. I remain actively involved in understanding the molecular and physiological functions of PABPs and how they are regulated.Project activity
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Identification and characterization of heart RNA-binding protein-mediated gene expression and its dysregulation in obesity-induced Diabetic Cardiomyopathy (DCM). (Collab. with Dr. Robert Young (Usher Institute, UoE)
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Quantification and mechanistic characterisation of the extensive post-transcriptional regulation underpinning adipogenesis in human health and obesity. [Collab. with Dr. Tuomas Kilpelainen (CBMR, Uni. Copenhagen), Prof. Roland Stimson (CVS, UoE) and Dr. Alex Von Kriegsheim (IGC, UoE)
Current project grants
4-year Biomedical Science PhD studentship (Sep 24 - Aug 28) - ''Defining the role of PABPC4 in regulating gene expression to maintain lipid homeostasis’
Awarded amount: ~£200k
University of Edinburgh
"Identifying mRNA 3’UTR and 5’UTR region cardiometabolic GWAS variants and quantifying their effect on the post-transcriptional regulation of gene expression underpinning human adipogenesis."
Awarded amount: £21,724
British Heart Foundation REA3 Pump Prime grant
"In vivo, genome-wide identification of the post-transcriptional regulation in heart that underpins the life-course of obesity-induced diabetic cardiomyopathy."
Awarded amount: £5,000
British Heart Foundation REA3 Pump Prime grant
Past project grants
"In vivo, genome-wide identification of the post-transcriptional regulation in heart and skeletal muscle that underpins the life-course of obesity-induced diabetes and cardiovascular disease"
Awarded amount: £28,632
British Heart Foundation REA3 Pump Prime grant
“Does PABP4 control diet-induced obesity, by acting as a master regulator of metabolism-related gene expression?”
Awarded amount: £545,841
BBSRC Project Reference: BB/R004668/1 [Dec 2017 - Dec 2020]
Lead author and Co-I (PI, Prof. Nicola Gray; Co-I, Prof. Nik Morton)
"Can histone code-like 'switches' govern the multi-functionality of RNA-binding proteins?"
Awarded amount: £723,957
BBSRC Project Reference: BB/P022065/1 [Sep 2017 - Sep 2020]
Lead author/Co-Investigator (PI, Prof. Nicola Gray; Co-I, Dr. Atlanta Cook)
“Poly(A)-binding proteins highlight the importance of regulated mRNA translation and stability in determining a functional maternofetal interface”
Awarded amount: £1.4M
MRC Program Grant [2012-2017]
Joint Co-Author (PI, Prof. Nicola Gray)
Organiser
Translation UK 2010: Biochemical Society Focused meeting
Translation UK 2025
EdiRNA (RNA Society-sponsored salon)