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{Park:2023:10.1038/s44161-023-00365-0,
author = {Park, KC and Crump, NT and Louwman, N and Krywawych, S and Cheong, YJ and Vendrell, I and Gill, EK and Gunadasa-Rohling, M and Ford, KL and Hauton, D and Fournier, M and Pires, E and Watson, L and Roseman, G and Holder, J and Koschinski, A and Carnicer, R and Curtis, MK and Zaccolo, M and Hulikova, A and Fischer, R and Kramer, HB and McCullagh, JSO and Trefely, S and Milne, TA and Swietach, P},
doi = {10.1038/s44161-023-00365-0},
journal = {Nature Cardiovascular Research},
pages = {1221--1245},
title = {Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation},
url = {http://dx.doi.org/10.1038/s44161-023-00365-0},
volume = {2},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Propiogenic substrates and gut bacteria produce propionate, a post-translational protein modifier. In this study, we used a mouse model of propionic acidaemia (PA) to study how disturbances to propionate metabolism result in histone modifications and changes to gene expression that affect cardiac function. Plasma propionate surrogates were raised in PA mice, but female hearts manifested more profound changes in acyl-CoAs, histone propionylation and acetylation, and transcription. These resulted in moderate diastolic dysfunction with raised diastolic Ca2+, expanded end-systolic ventricular volume and reduced stroke volume. Propionate was traced to histone H3 propionylation and caused increased acetylation genome-wide, including at promoters of Pde9a and Mme, genes related to contractile dysfunction through downscaled cGMP signaling. The less severe phenotype in male hearts correlated with β-alanine buildup. Raising β-alanine in cultured myocytes treated with propionate reduced propionyl-CoA levels, indicating a mechanistic relationship. Thus, we linked perturbed propionate metabolism to epigenetic changes that impact cardiac function.
AU  - Park,KC
AU  - Crump,NT
AU  - Louwman,N
AU  - Krywawych,S
AU  - Cheong,YJ
AU  - Vendrell,I
AU  - Gill,EK
AU  - Gunadasa-Rohling,M
AU  - Ford,KL
AU  - Hauton,D
AU  - Fournier,M
AU  - Pires,E
AU  - Watson,L
AU  - Roseman,G
AU  - Holder,J
AU  - Koschinski,A
AU  - Carnicer,R
AU  - Curtis,MK
AU  - Zaccolo,M
AU  - Hulikova,A
AU  - Fischer,R
AU  - Kramer,HB
AU  - McCullagh,JSO
AU  - Trefely,S
AU  - Milne,TA
AU  - Swietach,P
DO  - 10.1038/s44161-023-00365-0
EP  - 1245
PY  - 2023///
SN  - 2731-0590
SP  - 1221
TI  - Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation
T2  - Nature Cardiovascular Research
UR  - http://dx.doi.org/10.1038/s44161-023-00365-0
VL  - 2
ER  -
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