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)
Nick Crump (he/him)
Kay Kendall Leukaemia Fund Intermediate Fellow
Jinglin Zhou (he/him)
Jinglin Zhou (he/him)
PhD student
Jason Taslim (he/him)
Jason Taslim (he/him)
Research assistant
Sophie Ball (she/her)
Sophie Ball (she/her)
PhD student
Funders
Research Publications
Results
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Journal articleGodfrey L, Crump NT, Thorne R, et al., 2019,
DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation
, Nature Communications, Vol: 10, ISSN: 2041-1723Enhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to demarcate potentially active enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (H3K79) di or trimethylation (me2/3) (which we name H3K79me2/3 enhancer elements or KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblastic leukemias (ALL). Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is required for maintaining chromatin accessibility, histone acetylation and transcription factor binding specifically at KEEs but not non-KEE enhancers. We go on to show that H3K79me2/3 is essential for maintaining enhancer-promoter interactions at a subset of KEEs. Together, these data implicate H3K79me2/3 as having a functional role at a subset of active enhancers in MLL-AF4 leukemia cells.
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Journal articleDancy BM, Crump NT, Peterson DJ, et al., 2012,
Live-Cell Studies of p300/CBP Histone Acetyltransferase Activity and Inhibition
, CHEMBIOCHEM, Vol: 13, Pages: 2113-2121, ISSN: 1439-4227- Author Web Link
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- Citations: 45
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Journal articleCrump NT, Hazzalin CA, Bowers EM, et al., 2011,
Dynamic acetylation of all lysine-4 trimethylated histone H3 is evolutionarily conserved and mediated by p300/CBP
, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 7814-7819, ISSN: 0027-8424- Cite
- Citations: 92
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Journal articleBowers EM, Yan G, Mukherjee C, et al., 2010,
Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor
, CHEMISTRY & BIOLOGY, Vol: 17, Pages: 471-482, ISSN: 1074-5521- Author Web Link
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- Citations: 528
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Journal articleWorrall JAR, Gorna M, Crump NT, et al., 2008,
Reconstitution and analysis of the multienzyme <i>Escherichia coli</i> RNA degradosome
, JOURNAL OF MOLECULAR BIOLOGY, Vol: 382, Pages: 870-883, ISSN: 0022-2836- Cite
- Citations: 68
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