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:2008:10.1007/4735_2007_0254,
author = {Crump, NT and Han, YT and Mahadevan, LC},
doi = {10.1007/4735_2007_0254},
journal = {Topics in Current Genetics},
pages = {283--297},
title = {Stress-activated MAP kinases in chromatin and transcriptional complexes},
url = {http://dx.doi.org/10.1007/4735_2007_0254},
volume = {20},
year = {2008}
}
TY - JOUR
AB - Stress-activated MAP kinases (SAPKs) are activated by stressors or by certain physiological stimuli and mediate an intracellular response appropriate to the change in environment. Long-term adaptation requires reprogramming of transcription and one of the most significant actions of SAPK cascades is therefore induction of gene expression. SAPKs and their downstream kinases phosphorylate many chromatin-associated and transcription factors. Further, they can induce localised histone modification by regulating histone acetyltransferases and deacetylases. p38/SAPK2 also elicits phosphorylation of the nucleosomal proteins histone H3 and HMGN1 (previously HMG-14) via the downstream mitogen- and stress-stimulated kinases MSK1/2. Finally, recent evidence indicates a novel non-enzymatic SAPK function in transcriptional complexes, suggesting a more structural role. The yeast SAPK Hog1p is recruited to a proportion of its target genes on activation and localises beyond the promoter into coding regions. The observation that Hog1p interacts with elongating RNA polymerase II in addition to several transcriptional elongation factors has led to the suggestion that this SAPK may behave like an elongation factor at some target genes. The generality of this new function is discussed. © 2007 Springer-Verlag Berlin Heidelberg.
AU - Crump,NT
AU - Han,YT
AU - Mahadevan,LC
DO - 10.1007/4735_2007_0254
EP - 297
PY - 2008///
SN - 1610-2096
SP - 283
TI - Stress-activated MAP kinases in chromatin and transcriptional complexes
T2 - Topics in Current Genetics
UR - http://dx.doi.org/10.1007/4735_2007_0254
VL - 20
ER -