Matthew Brook

Principal Investigator (UoE/CVS) and Lecturer (UoE/ZJE)

  • Centre for Cardiovascular Science

Contact details

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

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.

Joint Coordinator of Years 3&4 for the Integrated Biomedical Sciences (BMS) and Biomedical Bioinformatics (BMI) degree programmes.

Course Organiser for "Integrated Biomedical Science 4 (IBMS4)" and "Future Perspectives" 4th year courses.

Open to PhD supervision enquiries?

Yes

Areas of interest for supervision

https://www.ed.ac.uk/biomedical-sciences/postgraduate-studying/fully-funded-4-year-phd-studentships-in-biomedical#uoe_featurebox_ebdb80ef0bd095e27510a996efde8d723

Fully funded 4 Year PhD studentships in Biomedical Sciences (project details below)

Project 1: Defining the role of PABPC4 in regulating gene expression to maintain lipid homeostasis. 

Project 2: Mechanistic characterisation of regulation of PABPC1 by post-translational modification in response to nutrient availability

Applications are invited from outstanding students wishing to pursue a 4 Year PhD studentship in Biomedical Sciences from September 2024.

Based in the Edinburgh Medical School: Biomedical Sciences, University of Edinburgh you will have the opportunity to work with leading research groups while also developing your skills in transnational education. The studentships are fully funded for 4 Years including full fees (home or overseas), UKRI-level stipend and generous research costs. 

Alongside their PhD project, students will be supported in the development of their skills in TNE towards AFHEA accreditation. This will include short (typically 2 visits totalling 4-6 weeks per year) research and educational visits to our ZJE Joint Institute in China supported by their PhD supervisory team.

Applicants must contact me to discuss projects before submitting their application.

Candidates must meet University of Edinburgh PhD requirements including English language proficiency and acceptance is conditional on award of 2:1 degree classification (or similar) in a Biomedical related undergraduate Honours degree programme.

How to apply

To apply, email a single PDF document to ZJEPGSupport@ed.ac.uk by 12 noon on Friday 29th March 2024 that includes:

  1. your CV
  2. a 1 page statement of why you wish to pursue a PhD, including a ranking of up to 3 projects you are interested in following your discussion with prospective supervisor(s)
  3. a 1 page statement of how developing your transnational educational skills as part of your PhD will support your longer term career aspirations.  

Shortlisted candidates will have the opportunity to meet further with prospective PhD supervisors of their ranked projects at interview.

 

Project 1: Defining the role of PABPC4 in regulating gene expression to maintain lipid homeostasis.

Contact

Matt.Brook@ed.ac.uk

Name, location and email of co-applicants (Supervisory Team)

Prof. Nicola Gray (CRH/IRR)

Prof. Robert Semple (CVS)

Project description

PABPC4 is a poorly characterised RNA-binding protein whose genetic locus is strongly associated in human genetic association studies to metabolic disease traits (e.g. cholesterol and triglyceride levels, type 2 diabetes), with some associations sexually dimorphic. Population genetic studies (gnomAD) moreover indicate clear selection against heterozygous loss of function in the wider population. PABPC4 is a close homologue of PABPC1, which binds to mRNA poly(A) tails and regulates multiple facets of mRNA translation and turnover, but PABPC4 molecular functions, RNA targets, and role in mammalian physiology remain to be determined.

Importantly, our (Brook/Gray) unpublished work has revealed sexually-dimorphic dysregulation of growth, body composition, and response to high-fat diet (HFD) of Pabp4-/- mice, with male, but not female, Pabpc4-/- mice being profoundly protected from HFD-induced obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD). Collectively these findings establish that genetic alteration of PABPC4 function and/or expression predisposes to the development of impaired lipid metabolism, obesity and associated pathologies in response to HFD. 

We hypothesise that PABPC4 is a master post-transcriptional regulator of sexually dimorphic metabolic gene expression programs. We will take advantage of complementary expertise in the new collaborative team to test this hypothesis via 3 major aims:

Aim 1: Elucidate the metabolic/physiological mechanisms and tissue aetiology of the obesity resistant/dyslipidaemic phenotype of Pabpc4-/- mice. Aim 2: Identify cell types and cellular pathways underlying the PABP4-dependent regulation of lipid/lipoprotein profiles and metabolic traits in mice. Aim 3: Identify functionally relevant PABPC4 mRNA targets and characterise their dysregulation in Pabpc4-/- mice.

Approaches used in project

The student will receive training in cutting-edge methods to study mouse in vivo metabolism (e.g. Sable Promethion indirect calorimetry/behaviour system) and ex vivo/in vitro cell metabolism (e.g. cellular respiration). The identification of PABP4 targets and regulated pathways will require combinations of transcriptomics, proteomics (proteome regulation, protein interactome mapping) and post-transcriptional regulation of gene expression studies (e.g. RNA-binding protein function, RNA target identification).

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 and use of human genetic association data, as required.

Relevant references for project background

1.    J. Wu, R. X. Yin, T. Guo, Q. Z. Lin, S. W. Shen, J. Q. Sun, et al. (2015) Gender-specific association between the cytoplasmic poly(A) binding protein 4 rs4660293 single nucleotide polymorphism and serum lipid levels. Mol Med Rep. 12: 3476-3486 [PMID:26005159]

2.    L. A. Passmore and J. Coller (2022) Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression. Nat Rev Mol Cell Biol. 23(2): 93-106. [PMID:34594027]

3.    Fátima Gebauer, Thomas Schwarzl, Juan Valcárcel & Matthias W. Hentze (2021) RNA-binding proteins in human genetic disease. Nature Reviews Genetics. 22:185–198 [PMID: 33235359]

4.    Kelaini S, Chan C, Cornelius VA, Margariti A. (2021) RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease. Biology (Basel). 10(5):366. [PMID: 33923168]

5.    Van Nostrand EL, Pratt GA, et al. (2020) Principles of RNA processing from analysis of enhanced CLIP maps for 150 RNA binding proteins. Genome Biology. 21(1):90. [PMID: 32252787]

 

Project 2: Mechanistic characterisation of regulation of PABPC1 by post-translational modification in response to nutrient availability

Contact

Matt.Brook@ed.ac.uk

Name, location and email of co-applicants (Supervisory Team)

Dr. Di Chen (ZJE Institute, China)

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

Natasha Arzoo (PhD Student - Co-Supervised by Dr. Robert Young (Usher Institute, UoE) [Pakistan HEC Scholarship]

Rupashri Balaraman (MSc student)

Yuhan Qin (BSc student)

 

Honglin Yu (PhD Student ZJE Institute, China - Co-Supervisor with Dr. Di Chen (ZJE Institute)

Qizhe Shao (PhD Student ZJE Institute, China - Co-Supervisor with Dr. Di Chen (ZJE Institute)

Junping Shi (PhD Student ZJE Institute, China - Co-Supervisor with Dr. Robert Young (Usher Institute, UoE) and Dr. Xianghua Li (Sanger Institute, Cambridge)

Hongling Liu (PhD Student - Co-Supervisor with Prof. Nik Morton (PI) (UoE/Nottingham-Trent University), Prof. Kei Sakamoto (CBMR, Uni. Copenhagen)

Triin Ounapuu (PhD Student - Co-Supervisor with Prof. Nicola Gray (PI))

 

Past PhD students supervised

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

  1. 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)

  2. 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

"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)