News at the BCGB
Joined BCGB, Chemistry & Nucleic Acids Forum - interdisciplinary workshop on imaging (protein, nucleic acid and tissues) on 23rd of January 9:30am-1:30pm in CPD forum.
Open to any BCGB members interested in imaging.
We will organise a few technical presentations of different types of imaging (agenda to follow) but we would like this to be a workshop addressing our community questions and problems. Can you please volunteer a question/problem within a remit of imaging that you would like to discuss with our community and look for solutions, collaborations, future funding applications.
An example of such problem to discuss is: reliance for proteins, PTMs, R-loops detection by antibodies – how can we free our work from nonspecific antibodies?
Can you please email Aga (a.gambus@bham.ac.uk) and Andy (a.j.wilson.1@bham.ac.uk) with your suggestions of a problem to discuss.
This is first of the thematic workshops we are planning to run in 2024 to move from “let’s get to know each other” to “let’s work together on solving problems” stage. We are thinking of RNA focused meeting and structural biology focused meeting next. Please get in touch if specifically interested in contributing to either or if you would like to propose another subject.
Landmark paper by Professor Aga Gambus achieves cover spot in November 16 issue of Molecular Cell.
The structural mechanism of dimeric DONSON in replicative helicase activation.
See the Spotlight feature about this article on the research page for more details.
BCGB gained 6 new members following the 2023 BCGB symposium.
Professor Teresa Carlomagno from Biosciences is a structural biologist who combines a wide range of techniques, including NMR and X-ray spectroscopy, EM, Small-Angle-Scattering (SAS) and Electron Paramagnetic Resonance (EPR). She uses integrative structural biology to understand how proteins with flexible structure form higher order molecular complexes involved in RNA metabolism and in the regulation of gene expression.
Professor Hansong Ma is an expert in mitochondrial genetics. Her group develops tools and systems in Drosophila to study mitochondrial DNA transmission and maintenance. She previously demonstrated the Drosophila MCM helicase REC drives recombination of mitochondrial DNA to promote its repair at double strand breaks.
Professor Adam Croft from the Institute of Inflammation and Aging is investigating molecular mechanisms underlying rheumatoid arthritis. His main research interest is the development of novel immunotherapies for patients with autoimmune rheumatic and chronic inflammatory diseases, with a particular interest in the development of stromal cell (fibroblast) specific targets. His current projects include an analysis of the role of the transcription factor RUNX1 in driving synovial fibroblast pathogenicity in rheumatoid arthritis.
Dr Gianmarco Contino from the Institute of Cancer and Genomics is a clinician scientist actively working in the field translational oncology of gastrointestinal cancers and cancer genomic medicine. His research investigates structural variation of cancer genomes to exploit the vulnerabilities of aneuploidy and develop novel diagnostic and therapeutic strategies for upper gastrointestinal cancers.
Dr Hung-Ji Tsai is interested in how aneuploidy, an unbalanced genomic state with gain or loss of chromosomes, enables rapid adaptation to diverse environments. His research focus is to understand the distinct cellular processes driven by aneuploidy.
Dr Dario Balacco from dentistry comes from a gene regulation background and is studying bacteria that inhabit the skin in patients with Epidermolysis Bullosa. His previous research focused on applying biochemical and bioinformatic approaches to study and characterize pivotal proteins involved in the mRNA decay.
Grant success for BCGB members in 2023
Professor Aga Gambus, Professor Jo Parish and Dr Clare Davies were each awarded research grants that together total more than £1.6 million. Clare was awarded a Breast Cancer Now project grant to work on the role of PRMT5 in drug resistance in breast cancer. Jo was awarded a MRC project grant to study oncogenic human papillomaviruses (HPV) in human tonsil epithelia. Aga was awarded a BBSRC grant to work on the role of DONSON in DNA replication initiation (see the accompanying news item for more details). Just after this announcement Aga also published a landmark paper in Molecular Cell showing how DONSON functions by changing the conformation of the DNA replication initiation complex (see also the Spotlight feature on the BCGB Research page for more details).
The BCGB has 2 new professors
Eva Petermann and Aga Gambus have just been promoted to Professor.
Professor Eva Petermann
Professor Aga Gambus
The 6th BCGB Symposium on Genome Biology
The 6th Symposium on Genome Biology was a great success. Spread over 2 full days, it was the first full BCGB symposium to be held since 2019, before the onset of the COVID pandemic. With 13 national and international invited speakers it was attended by about 160 delegates, including the 13 sponsors, and it commenced with a recording greeting from Professor Neil Hanley who takes over as the head of the College of Medical and Dental Sciences on 1 September 2023. This was also the final symposium for the BCGB founding director Professor Constanze Bonifer, and for Professor Peter Cockerill, before they both retire at the end of 2023. Reflecting this, they were given the opportunity to invite two long term colleagues as the two Keynote speakers, Professors Ellen Rothenberg (Caltech) and Daniel Tenen (Harvard) (pictured below), who have known them both for many decades. See the Symposium report for more details and the Programme for a full list of speakers.
The 2023 BCGB Away Day
The 6th BCGB away day held on 9 June was well attended with about 35 attendees enjoying an afternoon walk in the Malvern Hills, pictured here on the summit of the Worcester Beacon.
After taking the train the University station, the group wound its way in glorious summer sunshine from the North Quarry car park, around North Hill and on the summit.
At the end of the walk the group enjoyed the beer garden at the Nags Head pub in Malvern, followed by a dinner in their restaurant. After organising all of the away days since 2015, this was the final one to be organised by Prof Peter Cockerill, seated here in the restaurant.
Three new members join the BCGB
The University of Birmingham recently created 2 new chair positions and an assistant professor position that are now aligned with the BCGB.
Professor Jason Parsons is joining from the Institute of Cancer and Genomic Sciences where he works on radiobiology.
Professor Joao Pedro de Magalhaes is joining from the Institute of Aging and Inflammation where he works on the genomics of ageing and rejuvenation.
Dr Jiarui Zhou in the School of Bioscience is using machine learning to address problems with biodiversity and toxicology
Publication highlights
Listed here are just a few selected highlights to illustrate the diverse nature of the internationally acclaimed work emanating from BCGB.
Aga Gambus published a landmark paper in Molecular Cell defining the role of DONSON in the initiation of DNA replication (see the Spotlight on the BCGB Research page for more details)
Constanze Bonifer published a pioneering method in Nature Communications that makes it possible to perform global identification of the transcriptional enhancers that control cell differentiation across consecutive stages from embryonic stem cells to mature blood cells. This technology is based on extracting fragments of DNA from active open chromatin regions and cloning them into cells in the form of expression vectors where the presence of fluorescent proteins is a marker of enhancer activity. (Nature Commun 14:267 (2023). Edginton-White B, et al. A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification.)
Matthias Soller had a publication in Nature Communications based on studies of drosophila showing that methylation of RNA plays a role in neuronal memory. This work demonstrated that the ribose adjacent to the mRNA cap can be methylated, which directs localisation of mRNA at neuronal synapses. Flies lacking this pathway were found to be deficient in reward learning. (Nature Commun 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.).
Ferenc Mueller led the DANIO-CODE consortium in a Nature Genetics publication representing a comprehensive genetic atlas defining 140,000 regions of DNA involved in regulating gene expression in zebrafish. A team of 27 laboratories performed whole genome analyses on 1802 samples to define gene regulatory networks controlling multiple stages of zebrafish development (Nature Genet 54:1037-1050 (2022). Baranasic D, et al. Multiomic atlas with functional stratification and developmental dynamics of zebrafish cis-regulatory elements.)
Martin Higgs published ground-breaking work in Molecular Cell by showing that the DNA repair protein BODL1 is able to recruit SETD1A which methylates histone H3K4 at DNA double strand breaks, thereby promoting binding of RIF1 that prevents further damage via DNA resection (Molecular Cell 82:1924-1939 e1910 (2022). Bayley R, et al. H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ.).
Grant Stewart published the basis of a newly identified genetic disease in The Journal of Clinical Investigation. This study demonstrated that the helicase RECQL1 is required for the repair of DNA damage mediated by topoisomerases (J Clin Invest 132 (2022). Abu-Libdeh B, et al. RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1.)
See the Publications section for a wider selection of major BCGB publications from recent years.
Research grant funding highlights in 2022
Members of BCGB continue to be highly successful in attracting major grant funding. Listed here are a few of the recent successes:
In 2022 Jo Morris secured more than £4.9 million from the Wellcome Trust, the MRC and Horizon Europe to better understand DNA replication and repair.
Eva Petermann and Jo Parish were also awarded £1.2 million by the MRC in 2022 to better understand the role of oncogene activation and genomic instability in cancer initiation.
In 2022 Andrew Beggs was awarded a £1.5 million MRC Senior Clinical Fellowship to continue his research using organoid models to study mechanisms of treatment resistance in colorectal cancer.
Post-lockdown report from BCGB (September 2021)
The last year and a half has been difficult for everyone, and especially hard for research labs that had to endure complete laboratory shut-downs for many months and severely restricted access to labs and offices at other times. However, that does not mean we have been unproductive. While working from home many of our members used this time to publish research articles based on data that they had already accumulated before the COVID19 pandemic struck. This made a substantial contribution to the University of Birmingham’s REF submission with many of these outputs ranked internally as 4 star publications. It is impossible to list them all here but here are just some of the highlights:
In the area of Epigenetics and Gene Regulation, the Bonifer/Cockerill group had a string of papers covering both Cancer Genomics and Molecular Immunology. Continuing on the theme of gene regulation and epigenetics in acute myeloid leukaemia (AML), which produced a Nature Genetics paper on gene regulatory networks in AML in 2019, Potluri et al showed in Cell Reports in 2021 that the transcription factor WT1 mediates oncogenic signalling to control AML growth. In a study in 2020, Chin et showed in Experimental Hematology that RUNX1/ETO and mutant KIT collaborate to re-programme transcription in AML with t(8;21) translocations, while Nafria et al showed in 2020 in Cell Reports that RUNX1-ETO interferes with normal RUNX1 binding to block early myeloid cell development. Kellaway et al showed in Haematologica in 2021 that RUNX1-EVI1 disrupts the gene regulatory networks controlling differentiation in AML with t(3;21) translocations, and also showed in Life Science Alliance in 2021 that different mutant RUNX1 oncoproteins re-program different differentiation pathways. Daniel Coleman’s contribution to the Nature Genetics paper was also acknowledged when he was awarded a Goldman Fellowship in 2021 by Leukaemia UK.
On the T cell front, Bevington et al published 3 landmark papers on gene regulation and epigenetics during T cell differentiation. One study in EMBO in 2020 revealed that T cell differentiation is actually initiated by IL-2 and IL-7 when naïve T cells are activated the first time, making cells receptive to differentiation factors which are only expressed much later. A collaboration with David Wraith in Cell Reports in 2020 defined the molecular basis of a peptide de-sensitisation therapy used in Multiple Sclerosis patients that renders auto-immune cells tolerant. A collaboration with David Withers in Frontiers in Immunology in 2021 defined the molecular basis of immunological memory by using antigen-specific T cells to show that memory T cells acquire stable epigenetic priming at immune response genes in response to antigen.
Also in the field of gene regulation in leukaemia, the Stankovic lab made major advances in the field of chronic lymphocytic leukemia (CLL). Kwok et published in Blood in 2020 the molecular basis for spontaneous regression in CLL. Marwon Kwok’s contribution was recognised with the Hamblin prize for the best CLL paper in 2020, the Trainee prize from the Royal College of Pathologists, and a 3 year fellowship from CRUK to study at Harvard.
With a change of subject now to zebrafish, the Mueller lab showed in Developmental Cell in 2021 that the germ plasm determining factor Tdrd7 controls the development of the germ plasm from primordial germ cells by programming transcriptional networks that govern cell fate decisions between germ cells and somatic cells. In a second study in Nature Communications in 2020, Nepal et al showed that many gene promoters in zebrafish, and also humans, utilise 2 distinct classes of transcription initiation sequences within individual promoters that are differentially regulated during the transition from maternal to zygotic gene expression during embryogenesis. Also in zebrafish, Rui Monteiro showed in Communications Biology that a conserved enhancer controlling the GATA2 gene is required for development of both blood cells and endothelial cells.
In one of 2 significant publications involving insect models, the Badenhorst group used drosophila as a model of inflammation to publish a study in Life Science Alliance in 2020 to show that oxidised dietary unsaturated fatty acids activate pro-inflammatory signalling pathways linked to JNK that phosphorylate the transcription factor FOXO, a transducer of insulin signalling, and render it unresponsive to insulin signalling.
In a study looking at honey bees, a study from the Soller group in Scientific Reports in 2021 revealed that the devastating effects of widely used neonicotinoid insecticides can be linked to changes in gene expression and increased susceptibility to bacterial infections.
A study of bacterial gene transcription published by the Grainger lab in Nature Microbiology in 2021 identified an abundant class of symmetrical bidirectional promoters that regulate divergent genes in E.Coli and in Archaea.
In the area of DNA replication and repair, the Stewart lab showed in Nature Communications in 2020 that the balance between early and late DNA replication is controlled by DONSON and FANCM associating with different replication origins. On a similar theme, the Akerman lab showed in Nature Communications in 2020 that different cell types share a core of replication origins that are defined as G-rich origins. In another study in The Journal of Clinical Investigation from the Stewart and Higgs labs in 2020, they showed that germline mutations in the RBBP8 gene, a regulator of homologous recombination during DNA repair, are responsible for a subset of early onset breast cancers. A study from the Saponaro lab showed in Cell Reports in 2021 that persistent transcription during DNA replication leads to a delay of replication timing of these transcribed regions. A team effort from several groups in BCGB, led by Paloma Garcia and published in EMBO Reports in 2021, showed that MYBL2 functions to suppress replication stress and genome instability in stem cells. A study from the Petermann and Morris labs in Nature Communications in 2020 identified the priming polymerase PrimPol as factor that leaves gaps in replicated DNA where replication is stalled by bulky DNA adducts, which require post-replication repair via DNA resection by RAD51 and homologous recombination.
Finally on the COVID19 front, Pawel Grzechnik joined a team of UoB chemists and virologists to develop molecules that form supramolecular barrel structures capable of blocking viral replication. The characterisation of these novel therapeutics was published in 2021 in Angew Chem Int Ed Engl.
Promotions and awards for BCGB members in 2020 and 2021
Jo Parish and Andrew Beggs were promoted to Professor.
Eva Petermann and Aga Gambus were promoted to Reader.
Dr Martin Higgs, Dr Marco Saponaro, and Dr Ildem Akerman were promoted to Senior Lecturer.
Well done to all.
Professor Jo Parish
Professor Andrew Beggs
Dr Eva Petermann
Dr Aga Gambus
Dr Martin Higgs
Dr Marco Saponaro
Dr Ildem Akerman
In 2019, Professor Jo Morris published a paper in Nature describing a novel mechanism regulating the structure of the BRCA1 protein and how mutations in breast cancer prevent the BRCA1 protein from adopting the correct structure. BRCA1 normally protects the genome from DNA damage and this function is controlled by an isomerase that puts a bend in the BRCA1 protein. The Morris laboratory showed that some mutations occur in the isomerisation site and bypass this mode of regulation, and block normal BRCA1 function.
Professor Jo Morris
Promotions and awards for BCGB members in 2019
Dr Jo Parish and Claire Davies were both promoted to reader, in recognition of their outstanding progress as rising stars in research. Clare was recently awarded £1.4 million by the CRUK to study arginine methylation in cancer, based on high profile publications in Molecular Cell and Cell Reports, while Jo was awarded a MRC grant to study HPV based on her long term research and extensive publications in the area of viral gene regulation and replication.
Dr Clare Davies
Dr Jo Parish
Continuing outstanding grant success
The strong recent track record of BCGB members at winning major grant funding has continued with the award of ~ £10 million in grant funding in the first few months of 2019.
These awards include
- £4 million for 3 CRUK programme grants for Eva Petermann, Jo Morris and Tanja Stankovic
- £3.4 million for 2 Wellcome Trust grants for Ian Tomlinson and Aga Gambus
- Research Council Project grants for Dr Marco Saponano, Dr Eva Petermann, Dr Sheela Jayaraman, and for Professor Conny Bonifer together with Professor Peter Cockerill.
New drug targets identified for personalised medicine in acute myeloid leukaemia
The group of Constanze Bonifer and Peter Cockerill have revealed the roles that different types of gene mutations play in causing acute myeloid leukaemia in a study that was the culmination of a decade’s research. The findings of the team mean that doctors are now one step closer to being able to provide tailored and targeted treatment specific to individual AML patients. By identifying the specific mutations present in each AML patient and gathering genome-wide data on each of them, they were able to identify the main trigger points where critical mutations feed through to other genes that control the cells’ identity and behaviour.
Crucially, AML cells from patients with the same types of mutations always show the same pattern of abnormal gene regulation when they become cancer cells. This means that personalised medicine will one day become a reality for AML patients, allowing a different drug to be given to treat each form of AML. This has already been validated for one common subtype in AML.
In collaboration with Professor Olaf Heidenreich’s team at Newcastle University, this team also found that a growth-promoting gene, called CCND2, was crucial for the survival of AML with t(8;21) translocations. The already approved breast cancer drug called palbociclib designed to inhibit CCDN2 was able to block AML tumour development - therefore identifying it as a drug that could be used to target and treat AML.
These results were just published in
Assi et al (2018). ‘Subtype-specific regulatory network rewiring in acute myeloid leukemia’. Nature Genetics. DOI: 10.1038/s41588-018-0270-1
Martinez-Soria et al. ‘The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukaemia transformation.’ Cancer Cell. DOI: 10.1016/j.ccell.2018.08.015
2019 BCGB away day trip to the Malvern Hills
This year we had our most ambitious BCGB away yet, with a hike up to the top of the Worcestershire Beacon, the highest point in the Malvern Hills. The biggest challenge of the trip was not the 200 m climb, but the weather. Luckily we missed the worst of the torrential rain that had been falling all day as we all headed down to Malvern on the train. Once on the walk we took shelter at St Anne’s well (pictured) until the rain stopped, and the mist lifted as we hiked to the top with views all around. We arrived at the top in atmospheric conditions with mist swirling all around, before walking back down to a dinner together in Malvern.
St Anne’s Well, Malvern (June 2019)
Worcestershire Beacon, the highest point in the Malvern Hills (June 2019)
2018 BCGB Away Day visit to Packwood House
The 2018 BCGB away day in the Warwickshire countryside was a great day out with over 40 of our members taking part. We started out in Lapworth with a walk along the Stratford Canal to the Elizabethan manor at the National Trust property at Packwood House, and finished with a dinner overlooking the Grand Union Canal.
2017 BCGB Away Day visit to Soho House
This event explored the industrial roots of Birmingham as the “Workshop of the World”. It began at Galton Bridge (built by Telford) and followed the route of the Birmingham Canal (built by Brindley). It included a visit to Soho House, the home of the 18th century industrialist Matthew Boulton. Soho house was famously the meeting place for the Lunar Society, a group that included James Watt, Erasmus Darwin, Josiah Wedgewood and Joseph Priestley, which met once a month to discuss science and philosophy.
2016 BCGB Away Day Walk in the Woods
Members of the BCGB enjoyed a walk in the Lickey Hills for their 2016 away day at Barnt Green.
2015 BCGB Bluebell Woods Walk
Pictured are members of BCGB who went on the walk through the bluebells in the Lickey Hills (May 2015)
