Areas of Research
Epigenetic regulation of myeloma
Multiple myeloma is in many ways a disease driven by inappropriate gene expression. It is characterised by the aberrant activation of gene regulatory elements known as enhancers, stimulating the upregulation of key oncogenes. Blocking this behaviour is therefore a promising strategy for myeloma treatment, and many therapeutic strategies directly or indirectly target gene regulatory pathways.
The lab studies the epigenetic regulation of gene expression, focused on the way these processes are dysregulated in multiple myeloma. We have a particular interest in understanding the role of oncogenic enhancer activity in driving myeloma-specific transcriptional profiles, and identifying the factors responsible for this behaviour. A major goal of the lab is to identify potential therapeutic targets that could be developed as novel therapies for multiple myeloma.
We use a variety of high-throughput genomics techniques to study the chromatin landscape, including ChIP-seq, ATAC-seq and RNA-seq. We have optimised TOPmentation, a small cell-number technique that allows us to characterise the chromatin profile of myeloma patient samples. In addition, we use the 3C technology Micro-Capture-C to map the physical association of enhancers and promoters. By combining these techniques with genetic and pharmacological manipulation of myeloma cell lines, we are able to explore mechanistically enhancer function and regulation.
Mechanisms of myeloma drug resistance
Relapse is very common in myeloma after initial treatment. Patients typically enter remission following treatment, but invariably relapse, often with resistance to one or more of these drugs. There is therefore a pressing need to understand the mechanisms that drive this resistance to find ways to counteract it. We are working to identify and understand epigenetic mechanisms that drive drug resistance via changes in gene expression, which therefore may be reversed to resensitise cells to therapy.
Our team
Nick Crump (he/him)
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Nick Crump (he/him)
Kay Kendall Leukaemia Fund Intermediate Fellow
Jinglin Zhou (he/him)
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Jinglin Zhou (he/him)
PhD student
Jason Taslim (he/him)
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Jason Taslim (he/him)
Research assistant
Sophie Ball (she/her)
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Sophie Ball (she/her)
PhD student
Funders
Research Publications
Results
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Conference paperCross J, Smith AL, Jackson TR, et al., 2023,
PROM1/CD133 expression identifies highly proliferative MLL-AF4+blasts and correlates with a stem-like gene signature
, Publisher: GEORG THIEME VERLAG KG, Pages: 193-193, ISSN: 0300-8630 -
Conference paperPark KC, Crump N, Hulikova A, et al., 2022,
Elevated propionate/propionyl-CoA signalling drives Pde9a overexpression and contractile dysfunction through increased histone acetylation and propionylation
, 24th World Congress of the International-Society-for-Heart-Research, Publisher: ELSEVIER SCI LTD, Pages: S50-S50, ISSN: 0022-2828 -
Journal articleHulikova A, Park KC, Loonat AA, et al., 2022,
Alkaline nucleoplasm facilitates contractile gene expression in the mammalian heart
, Basic Research in Cardiology, Vol: 117, ISSN: 0300-8428Cardiac contractile strength is recognised as being highly pH-sensitive, but less is known about the influence of pH on cardiac gene expression, which may become relevant in response to changes in myocardial metabolism or vascularization during development or disease. We sought evidence for pH-responsive cardiac genes, and a physiological context for this form of transcriptional regulation. pHLIP, a peptide-based reporter of acidity, revealed a non-uniform pH landscape in early-postnatal myocardium, dissipating in later life. pH-responsive differentially expressed genes (pH-DEGs) were identified by transcriptomics of neonatal cardiomyocytes cultured over a range of pH. Enrichment analysis indicated “striated muscle contraction” as a pH-responsive biological process. Label-free proteomics verified fifty-four pH-responsive gene-products, including contractile elements and the adaptor protein CRIP2. Using transcriptional assays, acidity was found to reduce p300/CBP acetylase activity and, its a functional readout, inhibit myocardin, a co-activator of cardiac gene expression. In cultured myocytes, acid-inhibition of p300/CBP reduced H3K27 acetylation, as demonstrated by chromatin immunoprecipitation. H3K27ac levels were more strongly reduced at promoters of acid-downregulated DEGs, implicating an epigenetic mechanism of pH-sensitive gene expression. By tandem cytoplasmic/nuclear pH imaging, the cardiac nucleus was found to exercise a degree of control over its pH through Na+/H+ exchangers at the nuclear envelope. Thus, we describe how extracellular pH signals gain access to the nucleus and regulate the expression of a subset of cardiac genes, notably those coding for contractile proteins and CRIP2. Acting as a proxy of a well-perfused myocardium, alkaline conditions are permissive for expressing genes related to the contractile apparatus.
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Conference paperSchneider P, Arentsen-Peters STCJM, Crump NT, et al., 2022,
Establishment and Characterization of a Model of Acquired Resistance to DOT1L Inhibition in <i>KMT2A</i>-Rearranged Acute Lymphoblastic Leukemia Cells
, 64th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: ELSEVIER, Pages: 8760-8761, ISSN: 0006-4971 -
Conference paperHulikova A, Park KC, Loonat AA, et al., 2022,
Alkaline nucleoplasm facilitates contractile gene expressionin the mammalian heart
, Publisher: WILEY, Pages: 48-49, ISSN: 1748-1708
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