Research

BCGB 2019 Symposium attendees in the Wolfson common room

Research in BCGB spans research in diverse colleges, institutes, schools and centres across the University of Birmingham. This group of researchers is brought together by joint seminar and symposium programs, away days, and joint research studies.

The members of BCGB span these organisations:

2018 BCGB group on their Away Day

The highly collaborative research projects in BCGB cross many traditional boundaries but can be loosely group under the following headings where more detailed project-specific information can be found: 

Research themes 

Gene regulation and Epigenetics in development and disease

Table of current principal investigators active in gene regulation, epigenetics and genomics

NameResearch
Dr Ildem Akerman

Gene regulation in pancreatic beta cells

Dr Paul Badenhorst

The roles of ATP dependent chromatin remodelling enzymes

Professor Andrew Beggs

The identification of epigenetic biomarkers to stratify cancer diagnostics

Dr Saverio Brogna

Mechanisms connecting mRNA processing with translation and mRNA decay

Professor Teresa Carlomagno

Integrative structural biology 

Professor Adam Croft

Translational rheumatology

Dr Clare Davies

The role of arginine methylation in gene regulation and cancer

Professor Jonathan Frampton

The role of the transcription factor MYB in haemopoiesis and leukaemia

Dr Maarten Hoogenkamp

The role of the LMO transcriptional regulators in haemopoiesis and leukaemia

Dr Rui Monteiro

TGFb signalling in haematopoiesis and endothelial biology

Professor Ferenc Mueller

Chromatin programming and transcription regulation in Zebrafish

Professor Joanna Parish

Human papillomavirus gene regulation, genome stability and replication

Dr Matthias Soller

Mechanisms of pre-mRNA processing

Professor Bryan Turner

Histone modifications regulating gene expression

Dr Malgorzata Wiench

Regulation of gene expression by DNA methylation in development and cancer 

This theme is linked to:

RNA Biology

Table of current principal investigators active in gene regulation, epigenetics and genomics
NameResearch
 Dr Saverio Brogna  Mechanisms connecting mRNA processing with translation and mRNA decay
Professor Teresa Carlomagno  Integrative structural biology 
 Dr Matthias Soller  Mechanisms of pre-mRNA processing

DNA Replication and repair

List of current principal investigators active in DNA replication and repair research
NameResearch

Dr Agnieszka Gambus

Role of polyubiquitylation at the termination of eukaryotic DNA replication forks

Dr Paloma Garcia

The role of the MybL2 (B-Myb) protein in the maintenance of genome integrity

Dr Martin Higgs

The cellular response to DNA damage

Professor Jo Morris

Role of Ubiquitin ligases and ubiquitination in DNA repair and genome stability

Professor Jason Parsons

Radiobiology

Dr Eva Petermann

The cellular response to replication stress 

Dr Marco Saponaro

Transcription-mediated genome instability

Professor Tatjana Stankovic

The role of DNA damage response genes in leukaemia and lymphoma

Professor Grant Stewart

Genome stability and the DNA Damage Response

Professor Malcolm Taylor

Functional studies of the Ataxia Telangiectasia Mutated (ATM) protein

Dr Andrew Turnell

Viral regulation of replication and transcription

Cancer Biology

List of current principal investigators active in Cancer Biology
NameResearch

Dr Roland Arnold

Bioinformatics analyses of transcription in cancer

Professor Andrew Beggs

The identification of epigenetic biomarkers to stratify cancer diagnostics

Professor Constanze Bonifer

Transcriptional programming of chromatin in development and cancer.

Dr Gianmarco Contino

Cancer aneuploidy and structural variations

Dr Clare Davies

The role of arginine methylation in gene regulation and cancer

Professor Jonathan Frampton

The role of the transcription factor MYB in haemopoiesis and leukaemia

Dr Paloma Garcia

                        The role of the MybL2 (B-Myb) protein in the maintenance of genome integrity

Dr Maarten Hoogenkamp

The role of the LMO transcriptional regulators in haemopoiesis and leukaemia

Dr Claire Palles

Genetic predisposition to gastrointestinal cancer

Professor Joanna Parish

Human papillomavirus gene regulation, genome stability and replication

Professor Jason Parsons

Radiobiology

Professor Tatjana Stankovic

The role of DNA damage response genes in leukaemia and lymphoma

Professor Grant Stewart

Genome stability and the DNA Damage Response

Professor Malcolm Taylor

Functional studies of the Ataxia Telangiectasia Mutated (ATM) protein

Dr Malgorzata Wiench

Regulation of gene expression by DNA methylation in development and cancer 

Genetics and Genomics

List of current principal investigators active in Genetics and Genomics
NameResearch

Dr Dario Balacco

The skin microbiome seen in Epidermolysis Bullosa

Professor Andrew Beggs

The identification of epigenetic biomarkers to stratify cancer diagnostics

Professor Constanze Bonifer

Transcriptional programming of chromatin in development and cancer.

Dr Gianmarco Contino

Cancer aneuploidy and structural variations

Professor Joao Pedro de Magalhaes

Genomics of ageing and rejuvenation

Professor Hansong Ma

Mitochondrial genetics

Professor Ferenc Mueller

Chromatin programming and transcription regulation in Zebrafish

Dr Claire Palles

Genetic predisposition to gastrointestinal cancer

Dr Hung-Ji Tsai

The role of aneuploidy in eukaryotes

Bacterial genome studies

List of current principal investigators active in Bacterial genome studies
NameResearch

Professor Steve Busby

Gene regulation in Bacteria

Dr David Grainger 

Bacterial chromosome folding and gene regulation

Environmental toxicology studies

List of current principal investigators active in Environmental toxicology
NameResearch

Professor John Colbourne

Genetic mechanisms underlying responses of organisms to their environment

Dr Jiarui Zhou

Systems biology and the analysis of multi-omics data 

This theme is linked to

Computational Biology

List of current principal investigators active in Computational Biology
NameResearch

Dr Ildem Akerman 

Gene regulation in pancreatic beta cells

Dr Roland Arnold

Bioinformatics analyses of transcription in cancer

Professor Andrew Beggs 

The identification of epigenetic biomarkers to stratify cancer diagnostics

Professor Jean Baptiste Cazier

Director of the Centre for Computational Biology
Bioinformatics, Data Science for Life Sciences, Precision Medicine, Population Diversity

Professor Adam Croft

Translational rheumatology

Professor Joao Pedro de Magalhaes

Genomics of ageing and rejuvenation

Dr Deena Gendoo

Bioinformatics characterization of preclinical disease models and their applications in therapy

Dr Shan He

Complex network analysis and modelling applied to biomedical problems

Dr Lindsey Leach

Statistical methods for the analysis of genetic and genomic data

Professor Zewei Luo

Strategies for dissecting complex quantitative and disease traits

Dr Csilla Varnai

Bioinformatics and 3D organisation of genome

Dr Jiarui Zhou

Systems biology and the analysis of multi-omics data 

 

Research Highlights

Spotlight on the role of DONSON in kick-starting DNA replication at origins of replication

A collaboration between Aga Gambus in Birmingham and Alessandro Costa in London, with contributions from Grant Stewart, Birmingham, has revealed new insights into how DNA replication helicases switch from an inactive form to an active form at DNA origins of replication. High resolution electron microscopy showed how dimers of the protein DONSON (shown here in purple in the centre) bind in between two inactive DNA replication helicases at DNA origins and load symmetrically two helicase activators: the GINS complex. This leads to a conformational change in the complexes, resulting in rotation of the MCM helicases, and the initiation of DNA replication.

Molecular Cell  Oct 10:S1097-2765(23)00761-X  (2023). Cvetkovic MA, P Passaretti, A Butryn, A Reynolds-Winczura, G Kingsley, A Skagia, . . .G Stewart, A Gambus and A Costa. The structural mechanism of dimeric DONSON in replicative helicase activation. 

Image of DONSON at a DNA replication fork

Spotlight on marrow failure in a zebrafish model of GATA2 deficiency

The Monteiro group employed a zebrafish fish model to replicate what happens in patients who inherit the loss of one allele of the GATA2 gene who develop bone marrow failure and leukaemia. Zebrafish lacking a transcriptional enhancer needed for efficient GATA2 expression exhibit a gradual loss of myeloid blood cells, a skewing towards red blood cells, and an AML-like syndrome.

Cell Reports 42:112571 (2023). Christopher B Mahony, Lucy Copper, Pavle Vrljicak, Boris Noyvert, Chrystala Constantinidou, Sofia Browne, Yi Pan, Claire Palles, Sascha Ott, Martin R HiggsRui MonteiroLineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency. doi: https://doi.org/10.1016/j.celrep.2023.112571

A diagram of lineage skewing in GATA2-deficient zebrafish

GATA2 deficiency is a rare genetic bone marrow disorder in which patients are at increased risk of blood cancers. This is likely due to (i) GATA2-deficient blood stem cells in bone marrow producing significantly fewer immune cells used to fight infection, and (ii) the GATA2 gene mutation resulting in impaired activity of genes that are involved in repairing ongoing damage to their DNA.

In humans, GATA2 haploinsufficiency due to mutations in coding or enhancer regions causes hematopoietic disorders collectively referred to as GATA2 deficiency syndromes. 75% of patients with inherited germline GATA2 mutations develop early-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

In the zebrafish model employed here, both alleles of an enhancer controlling the gata2a locus were deleted. This generated a bona fide model of GATA2 deficiency that shows marrow hypocellularity, neutropenia, increased susceptibility to infections, and development of an AML-like phenotype in the adult kidney marrow. 

Spotlight on the role that mRNA modifications play in neuronal memory by trafficking mRNAs to synapses.

Diagram of mRNA localised at neuronal synapses

The Soller group has a publication in Nature Communications based on studies of drosophila showing that methylation of mRNA plays a role in neuronal memory. They showed that the ribose adjacent to the mRNA cap can be methylated. The main function of the cap is to protect mRNAs from degradation and to recruit translation initiation factors. However, modifications close to the cap can change the intra-cellular sites of translation (see also UoB press release).

Nature Communications 13:1209 (2022). Haussmann IU, et al. CMTr cap-adjacent 2'-O-ribose mRNA methyltransferases are required for reward learning and mRNA localization to synapses.

Spotlight on global analysis of enhancers that control blood cell development

New study uncovers the information encoded in our DNA required for the transcriptional control of blood cell development from embryonic stem cells

This publication from the Bonifer laboratory describes a novel genome-wide screen that identified and functionally characterised distinct subsets of gene regulatory elements that direct the different stages of the development of blood cells from embryonic stem cells (ESC)

Nature Communications 14:267 (2023). Edginton-White B, A Maytum, SG Kellaway, DK Goode, P Keane,. . . C BoniferA genome-wide relay of signalling-responsive enhancers drives hematopoietic specification.

doi: 10.1038/s41467-023-35910-9

Genome assay to define precise time course of activation of enhancers as detailed below.

This study of the genome investigated the functions of all of the regulatory elements within our DNA that are required to express our genes in the right cells, at the right levels, and at the right time. These regulatory elements are called enhancers and are scattered over large distances within the the 3 billion bases of DNA that make up the geneome. Enhancers also function to integrate multiple highly specific intrinsic and extrinsic signals, whereby most regulatory elements only function in a subset of cells. The Bonifer laboratory developed a whole genome assay able to define the precise time course of activation of enhancers, and their responses to external signals, during the stepwise development of blood cells from ESCs. These analyses identified thousands of differentially active enhancers able to stimulate a promoter across different stages of blood cell development from ESCs. It also showed that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of enhancers and promoters, many of which respond to the cytokine signals promoting cell differentiation towards blood cells. This work highlights the mechanisms of how and where extrinsic signals program a cell type-specific regulatory landscape driving hematopoietic differentiation.

This methodology, which can now be adapted to any ESC-derived cell type, also provides a way to investigate how gene expression is sometimes perturbed by mutations in enhancers or external signals which cause disease. To understand how genes respond to outside signals and are deregulated in disease, we need to know where these enhancer elements are, when they are active and how they function. 

Spotlight on protein modification crosstalk during DNA repair

Nature Communications 12: 6313 (2021). M-P Sanchez-Bailon M-P, S-Y Choi, ER Dufficy, K Sharma, GS McNee, E Gunnel, K Chiang, D Sahay, S Maslen, GS Stewart, JM Skehel, I Dreveny and CC Davies. Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair.


PRMT1 is an arginine methyltransferase that promotes genome stability and is upregulated in many cancers. Here, the group of Clare Davies identify the deubiquitylating enzyme USP11 as a new PRMT1 substrate, and that methylation of USP11 is required for double strand break repair. They also show that PRMT1 is a substrate for USP11, and that deubiquitylation of PRMT1 promotes PRMT1 activity towards MRE11, a component of the MRN complex, leading to efficient DNA end resection at break points. This study demonstrates the complexity of post-translational modifications that safe-guards our genome against DNA damage, but also suggests that hyper-activation could lead to chemo-resistance in cancer cells following chemo-therapy.

Spotlight on the Regulation of Carcinogenesis in Colorectal Cancer

Proc Natl Acad Sci U S A 118 (2021) e2011411118Andrijes R, RK Hejmadi, M Pugh, S Rajesh, V Novitskaya, M Ibrahim, ….. A Beggs,  F Berditchevski. Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer. doi: 10.1073/pnas.2011411118 

Bowel cancer patients expressing high levels of the membrane-bound protein TPSPAN6 are more likely to respond to treatment with Cetuximab, a monoclonal antibody inhibitor of the EGF receptor. Previously it has been difficult to identify bowel cancer patients likely to benefit from Cetuximab because only some of these patients respond to therapy, partly due to the fact a subset of these patients have KRAS mutations, and these patients may not even be eligible for Cetuximab. This study in PNAS from the groups of Fedor Berditchevski and Andrew Beggs reveals that TSPAN6 is a tumour suppressor that blocks the autocrine expression of membrane bound TGFa on vesicles that activate EGFR signalling. High levels of TSPAN6 expression are associated with enhanced sensitivity to Cetuximab, regardless of the KRAS mutation status. These finding may pave the way for personalised therapy in bowel cancer whereby TSPAN6 can be used as a biomarker to target patients most likely to benefit from Cetuximab, including those with KRAS mutations.

Spotlight on BRCA1 and DNA Replication

Nature  571: 521-527 (2019). Daza-Martin M, Starowicz K, Jamshad M, Tye S, Ronson GE, MacKay HL, Chauhan AS, Walker AK, Stone HR, Beesley JFJ, Coles JL, Garvin AJ, Stewart GS, McCorvie TJ, Zhang X, Densham RM, JR Morris. Isomerization of BRCA1-BARD1 promotes replication fork protection.  

Diagram of BRCA as described below

BRCA1 is a gene required for genome stability and is a frequent target of mutations in breast cancer. Here the group of Jo Morris shows that the functional activation of the BRCA1 protein involves a conformational change in its structure.

BRCA1 phosphorylation by CDK1/2 followed by isomerization by PIN1 enhances the ability of BARD1 to associate with RAD51 (brown) and thereby promotes replication fork protection.

Spotlight on Cancer Genomics

Nature Genetics 51:151-162 (2019). Assi SA, MR Imperato, DJL Coleman, A Pickin, S Potluri, A Ptasinska, . . . PN CockerillC Bonifer. Subtype-specific regulatory network rewiring in acute myeloid leukemia. 

Gene structure and regulation diagram as detailed below

A study by Constanze Bonifer and Peter Cockerill has revealed the roles that different types of gene mutations play in causing acute myeloid leukaemia. Epigenetic profiling of regulatory elements revealed that mutation-specific subsets of AML have distinct patterns of gene expression. Each subset was controlled by distinct gene regulatory networks linked to mutations in transcription factors and signalling molecules This research brings us one step closer to being able to provide tailored and targeted treatment specific to individual patients, increasing their chances of survival.