In this section
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.
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Nick Crump (he/him)
Kay Kendall Leukaemia Fund Intermediate Fellow
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Jinglin Zhou (he/him)
PhD student
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Jason Taslim (he/him)
Research assistant
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Sophie Ball (she/her)
PhD student
@article{Crump:2021:10.1038/s41467-020-20400-z,
author = {Crump, NT and Ballabio, E and Godfrey, L and Thorne, R and Repapi, E and Kerry, J and Tapia, M and Hua, P and Lagerholm, C and Filippakopoulos, P and Davies, JOJ and Milne, TA},
doi = {10.1038/s41467-020-20400-z},
journal = {Nature Communications},
title = {BET inhibition disrupts transcription but retains enhancer-promoter contact},
url = {http://dx.doi.org/10.1038/s41467-020-20400-z},
volume = {12},
year = {2021}
}
TY - JOUR
AB - Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin.
AU - Crump,NT
AU - Ballabio,E
AU - Godfrey,L
AU - Thorne,R
AU - Repapi,E
AU - Kerry,J
AU - Tapia,M
AU - Hua,P
AU - Lagerholm,C
AU - Filippakopoulos,P
AU - Davies,JOJ
AU - Milne,TA
DO - 10.1038/s41467-020-20400-z
PY - 2021///
SN - 2041-1723
TI - BET inhibition disrupts transcription but retains enhancer-promoter contact
T2 - Nature Communications
UR - http://dx.doi.org/10.1038/s41467-020-20400-z
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000670283600008&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR - https://www.nature.com/articles/s41467-020-20400-z
VL - 12
ER -