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{Hua:2021:10.1038/s41586-021-03639-4,
author = {Hua, P and Badat, M and Hanssen, LLP and Hentges, LD and Crump, N and Downes, DJ and Jeziorska, DM and Oudelaar, AM and Schwessinger, R and Taylor, S and Milne, TA and Hughes, JR and Higgs, DR and Davies, JOJ},
doi = {10.1038/s41586-021-03639-4},
journal = {Nature},
pages = {125--129},
title = {Defining genome architecture at base-pair resolution},
url = {http://dx.doi.org/10.1038/s41586-021-03639-4},
volume = {595},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - In higher eukaryotes, many genes are regulated by enhancers that are 104–106 base pairs (bp) away from the promoter. Enhancers contain transcription-factor-binding sites (which are typically around 7–22 bp), and physical contact between the promoters and enhancers is thought to be required to modulate gene expression. Although chromatin architecture has been mapped extensively at resolutions of 1 kilobase and above; it has not been possible to define physical contacts at the scale of the proteins that determine gene expression. Here we define these interactions in detail using a chromosome conformation capture method (Micro-Capture-C) that enables the physical contacts between different classes of regulatory elements to be determined at base-pair resolution. We find that highly punctate contacts occur between enhancers, promoters and CCCTC-binding factor (CTCF) sites and we show that transcription factors have an important role in the maintenance of the contacts between enhancers and promoters. Our data show that interactions between CTCF sites are increased when active promoters and enhancers are located within the intervening chromatin. This supports a model in which chromatin loop extrusion1 is dependent on cohesin loading at active promoters and enhancers, which explains the formation of tissue-specific chromatin domains without changes in CTCF binding.
AU  - Hua,P
AU  - Badat,M
AU  - Hanssen,LLP
AU  - Hentges,LD
AU  - Crump,N
AU  - Downes,DJ
AU  - Jeziorska,DM
AU  - Oudelaar,AM
AU  - Schwessinger,R
AU  - Taylor,S
AU  - Milne,TA
AU  - Hughes,JR
AU  - Higgs,DR
AU  - Davies,JOJ
DO  - 10.1038/s41586-021-03639-4
EP  - 129
PY  - 2021///
SN  - 0028-0836
SP  - 125
TI  - Defining genome architecture at base-pair resolution
T2  - Nature
UR  - http://dx.doi.org/10.1038/s41586-021-03639-4
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000659405400001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR  - https://www.nature.com/articles/s41586-021-03639-4
VL  - 595
ER  -
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