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{Hulikova:2022:10.1007/s00395-022-00924-9,
author = {Hulikova, A and Park, KC and Loonat, AA and Gunadasa-Rohling, M and Curtis, MK and Chung, YJ and Wilson, A and Carr, CA and Trafford, AW and Fournier, M and Moshnikova, A and Andreev, OA and Reshetnyak, YK and Riley, PR and Smart, N and Milne, TA and Crump, NT and Swietach, P},
doi = {10.1007/s00395-022-00924-9},
journal = {Basic Research in Cardiology},
title = {Alkaline nucleoplasm facilitates contractile gene expression in the mammalian heart},
url = {http://dx.doi.org/10.1007/s00395-022-00924-9},
volume = {117},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Cardiac 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.
AU  - Hulikova,A
AU  - Park,KC
AU  - Loonat,AA
AU  - Gunadasa-Rohling,M
AU  - Curtis,MK
AU  - Chung,YJ
AU  - Wilson,A
AU  - Carr,CA
AU  - Trafford,AW
AU  - Fournier,M
AU  - Moshnikova,A
AU  - Andreev,OA
AU  - Reshetnyak,YK
AU  - Riley,PR
AU  - Smart,N
AU  - Milne,TA
AU  - Crump,NT
AU  - Swietach,P
DO  - 10.1007/s00395-022-00924-9
PY  - 2022///
SN  - 0300-8428
TI  - Alkaline nucleoplasm facilitates contractile gene expression in the mammalian heart
T2  - Basic Research in Cardiology
UR  - http://dx.doi.org/10.1007/s00395-022-00924-9
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000780861200001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR  - https://link.springer.com/article/10.1007/s00395-022-00924-9
VL  - 117
ER  -
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