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Investigating KAT2A as a novel therapeutic target in neuroblastoma

The Pina lab is looking for a highly-motivated, technically-able and independent-thinking candidate to undertake a PhD project researching the role of histone acetyl-transferase KAT2A in neuroblastoma. The project will be supervised by Dr Cristina Pina (/people/cristina-pina) at the Department of Life Sciences of СʪÃÃÊÓƵ London (College of Health, Medicine and Life Sciences), and will be developed in collaboration with Professor Arturo Sala (/people/arturo-sala). The Pina group is part of the Centre for Genome Engineering and Maintenance (/research/Centres/Genome-Engineering-and-Maintenance), where Cristina Pina is the Cluster Lead for Cancer Mechanisms. Professor Sala is a specialist in translational neuroblastoma research, and a member of the Centre for Inflammation Research and Translational Medicine (/research/Centres/Inflammation-Research-and-Translational-Medicine).

The Pina lab specialises in epigenetic and transcriptional regulation of normal and malignant stem cell fate decisions, and has an interest in the role of histone acetyl-transferase KAT2A in cancer. The group has previously characterised KAT2A as a vulnerability in Acute Myeloid Leukaemia (doi: 10.1016/j.celrep.2016.09.079), its loss resulting in progressive depletion of leukaemia stem cells (doi: 10.7554/eLife.51754). KAT2A exerts its effects through 2 distinct complexes, SAGA and ATAC, which respectively control cell differentiation and biosynthetic programmes (doi: 10.1101/2020.05.14.096057). The Sala group has been involved in neuroblastoma research for over 20 years, contributing to the identification of oncogenes and tumour suppressor genes relevant to this cancer (doi: 10.1093/jnci/djp063; doi: 10.1038/cddis.2011.99; doi: 10.1158/1078-0432.CCR-15-2081; doi: 10.1074/jbc.M113.454280). Neuroblastoma is the most common solid tumour in children under the age of 5. It has a poor overall 5-year survival of <75%, which drops to <60% in high-risk disease.  High-risk disease is associated with amplification of the MYCN gene, which has been shown to partner KAT2A during development of the nervous system. Preliminary data from our group suggests that inhibition of KAT2A kills neuroblastoma cells with MYCN amplification, and may constitute a novel therapeutic strategy in neuroblastoma.

In this project, the successful candidate will use chemical and genetic ablation of KAT2A, and of components of SAGA and ATAC complexes, to dissect the cellular and molecular mechanisms by which KAT2A complexes sustain neuroblastoma cells. They will use 2D and organoid-culture systems and employ transcriptomic and chromatin profiling tools to analyse MYCN amplified and non-amplified cell lines and primary neuroblastoma samples, and to target differentiated and stem-like neuroblastoma cells.

Candidates will have a First or Upper Second-class BSc (Hons) degree or equivalent in Biology, Biomedical Sciences, Natural Sciences, Life Sciences, Genetics, Biochemistry or similar areas, with significant lab experience. An MSc qualification is desirable but not essential. Candidates will be very competent lab workers who value attention to detail, enjoy technical challenges and successfully persevere. They will have excellent oral and written communication skills, and will demonstrate the capacity to autonomously research, synthesise and critically evaluate relevant literature. They will successfully work independently and as part of a team, and will demonstrate a dedicated and flexible approach to work.

Informal enquiries can be made to Cristina Pina (cristina.pina@brunel.ac.uk) or Arturo Sala (arturo.sala@brunel.ac.uk). We look forward to hearing from you.

Individual histone modification roles in regulation of transcription and cell decision-making

We are looking for a highly-motivated, technically-able and independent-thinking candidate to undertake a PhD project exploring the role of individual histone modifications in nuclear organisation, regulation of transcription, and the process of stem cell fate decision in development, aging and disease. The project will be supervised by Dr Cristina Pina (/people/cristina-pina) and Prof Joanna Bridger (/people/joanna-bridger) at the Department of Life Sciences of СʪÃÃÊÓƵ London (College of Health, Medicine and Life Sciences). Both groups are part of the Centre for Genome Engineering and Maintenance (/research/Centres/Genome-Engineering-and-Maintenance), where Prof Bridger in Centre Director, and Dr Pina is the Cluster Lead for Cancer Mechanisms.

The Pina lab specialises in epigenetic and transcriptional regulation of normal (doi: 10.1038/ncb2442; doi: 10.1016/j.celrep.2015.05.016; doi: 10.1002/stem.2919) and malignant stem cell fate decisions (doi: 10.1016/j.celrep.2016.09.079; doi: 10.7554/eLife.51754; doi: 10.1101/2020.05.14.096057), with an interest in mechanisms of leukaemia initiation and progression. We use single-cell technologies, genome-wide transcriptional and epigenetic profiling with next-generation sequencing, and genetic and epigenetic editing of individual loci with CRISPR-Cas9-based tools, to investigate in vitro and in vivo models of stem cell fate decisions. The Bridger lab has long-standing expertise in the role of nuclear organisation in cell decisions during normal and pathological aging (doi: 10.1007/978-1-4899-8032-8_12; doi: 10.3389/fgene.2018.00623;  doi: 10.1139/bcb-2019-0096), and uses state-of-the-art imaging techniques (doi: 10.1007/978-1-4939-3530-7_24; doi: 10.3791/62017) to understand nuclear dynamics and genome stability.

In recent years, the Pina lab unveiled a role for histone acetyl-transferase KAT2A/Kat2a in stabilising the frequency at which individual genes are transcribed (doi: 10.7554/eLife.51754). We suggested that loss of Kat2a allows normal and malignant stem cells to drift away from their self-renewing state to initiate differentiation programmes (doi: 10.1002/stem.2919; doi: 10.7554/eLife.51754), resulting in diversification of cell types. Kat2a is responsible for acetylation of lysine 9 of Histone 3. It functions in 2 macromolecular complexes, SAGA and ATAC, which target distinct sets of genes and have additional histone modification activities, respectively H2AK120 and H2BK119 de-ubiquitination, and H4K5 acetylation. The relative contribution of the 2 complexes, and of their individual histone modifications, to the effects on transcription and cell fate, however, remain largely uncharacterised (doi: 10.1016/j.exphem.2020.10.003).

The successful candidate will specifically investigate the roles of H3K9ac and H4K5ac in the dynamics of locus activation and transcription and the consequences to stem cell differentiation systems. They will generate histone acetylation mutants or use Cas9-guided modification of candidate loci combined with single-molecule RNA-FISH to investigate the dynamic regulation of locus activity in mouse embryonic stem (mES) cells. Nuclear imaging will identify higher-order consequences to chromatin organisation. Modified mES cells will be studied in 2D and 3D self-renewal and differentiation systems to understand consequences to cell decision-making.

Candidates will have a First or Upper Second-class BSc (Hons) degree or equivalent in Biology, Biomedical Sciences, Natural Sciences, Life Sciences, Genetics, Biochemistry or similar areas, with significant lab experience. An MSc qualification is desirable but not essential. Candidates will be very competent lab workers who value attention to detail, enjoy technical challenges and successfully persevere. They will have excellent oral and written communication skills, and will demonstrate the capacity to autonomously research, synthesise and critically evaluate relevant literature. They will successfully work independently and as part of a team, and will demonstrate a dedicated and flexible approach to work.

Informal enquiries can be made to Cristina Pina (cristina.pina@brunel.ac.uk) or Joanna Bridger (Joanna/bridger@brunel.ac.uk). We look forward to hearing from you.

PhD projects for research students

• Individual histone modification roles in regulation of transcription and cell decision-making
• Funding for the Executive Dean’s PhD Studentship: Lineage tracing of blood stem cell development in embryo-like gastruloids

Research supervision

GRADUATE STUDENTS

2022-present: Ayona Johns - PhD Student (Lady Tata Memorial Trust International Scholar); Department of Life Sciences СʪÃÃÊÓƵ London

2022-present: Holly Davison - MPhil Student; Department of Life Sciences СʪÃÃÊÓƵ London

2021-present: Ana Carolina Borges - visiting PhD Student; Oswald Cruz Foundation (FIOCRUZ), Brazil

2021-2022: Liza Dijkhuis - visiting MSc research Student; University of Groningen, The Netherlands

2020-2021: Ralph Samarista - MPhil Student; Department of Life Sciences СʪÃÃÊÓƵ London

2020-2021: Debora della Martera - visiting MSc research Student; University of Bologna, Italy; co-supervisor

2017-2022: Chun-Wai Suen - PhD Student; Department of Genetics University of Cambridge

2017-2021: Shikha Gupta - Lady Tata Memorial Trust PhD Studentship; Department of Genetics University of Cambridge

2017-2021: Liliana Jesus Arede – Rosetrees Trust PhD Studentship; Department of Genetics University of Cambridge

2017-2018: Alice Taylor - MPhil Student; Cambridge Institute for Medical Research (Haematology)

2017-2018: Elena Foerner – visiting MSc research student; Bayreuth University, Germany; co-supervisor

2017: Rita Romano Adao – visiting MPharma Student; University of Lisbon, Portugal; co-supervisor

2013-2016: Naomi Moris – BBSRC DTP Student; University of Cambridge Department of Genetics; co-supervisor with Alfonso Martinez Arias

2012: Sabine Gogolok – CRUK Rotation PhD Student; University College London Cancer Institute

UNDERGRADUATE STUDENTS

09/2022-present: Isabel Ingleton - BSc Biosciences; СʪÃÃÊÓƵ London (Placement Year)

01/2021-08/2021: Holly Davison - BSc Biosciences; СʪÃÃÊÓƵ London (Placement Year)

10/2020-08/2021: Maximilian Mollenhauer-Starkl - BSc Life Sciences; СʪÃÃÊÓƵ London (Placement Year)

10/2019-05/2020: Ayona Johns - BSc Biosciences; СʪÃÃÊÓƵ London (Placement Year)

09/2018-06/2019: Oliwia Cyran – BSc in Biomedicine; King’s College London (Extra-Mural Research Year)

05/2018-08/2018: Laura Vinnenberg – BSc in Biotechnology; University of Munster, Germany (Extra-Mural Research Attachment)

04/2017-07/2017: Elena Foerner – BSc in Biotechnology; University of Bayreuth, Germany (Extra-Mural Research Attachment)

11/2016-04/2017: Selinde Wind – Medical Student; Free University of Amsterdam, Netherlands (Mandatory Research Attachment)

10/2016-01/2017: Svenja Kleinwaechter – BSc in Biology; University of Biel, Germany (Extra-Mural Research Attachment)