Contact

Nicholas Crump

  • Kay Kendall Intermediate Fellow

n.crump@imperial.ac.uk

Follow us on instagram (@crumplab)

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

The Kay Kendall Leukaemia Fund

Blood Cancer UK/ Matthew Wilson MM Fund

Imperial Health Charity

The Royal Society

Research Publications

Citation

BibTex format

@article{Crump:2023:10.1038/s41467-023-40981-9,
author = {Crump, NT and Smith, AL and Godfrey, L and Dopico-Fernandez, AM and Denny, N and Harman, JR and Hamley, JC and Jackson, NE and Chahrour, C and Riva, S and Rice, S and Kim, J and Basrur, V and Fermin, D and Elenitoba-Johnson, K and Roeder, RG and Allis, CD and Roberts, I and Roy, A and Geng, H and Davies, JOJ and Milne, TA},
doi = {10.1038/s41467-023-40981-9},
journal = {Nature Communications},
pages = {1--20},
title = {MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia},
url = {http://dx.doi.org/10.1038/s41467-023-40981-9},
volume = {14},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation.
AU  - Crump,NT
AU  - Smith,AL
AU  - Godfrey,L
AU  - Dopico-Fernandez,AM
AU  - Denny,N
AU  - Harman,JR
AU  - Hamley,JC
AU  - Jackson,NE
AU  - Chahrour,C
AU  - Riva,S
AU  - Rice,S
AU  - Kim,J
AU  - Basrur,V
AU  - Fermin,D
AU  - Elenitoba-Johnson,K
AU  - Roeder,RG
AU  - Allis,CD
AU  - Roberts,I
AU  - Roy,A
AU  - Geng,H
AU  - Davies,JOJ
AU  - Milne,TA
DO  - 10.1038/s41467-023-40981-9
EP  - 20
PY  - 2023///
SN  - 2041-1723
SP  - 1
TI  - MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
T2  - Nature Communications
UR  - http://dx.doi.org/10.1038/s41467-023-40981-9
UR  - https://www.ncbi.nlm.nih.gov/pubmed/37626123
UR  - https://www.nature.com/articles/s41467-023-40981-9
VL  - 14
ER  -
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