 n
the interview below, Dr. James Davie talks about his highly
cited work in histone modifications. According to a recent
analysis for in-cites, Dr. Davie’s work has entered the top
1% in terms of total citations in the field of Biology &
Biochemistry. Dr. Davie’s work also appears in the Molecular
Biology & Genetics and Multidisciplinary fields. Dr. Davie
is the Provincial Director of Research at CancerCare Manitoba,
the Director of the Manitoba Institute of Cell Biology, and
Professor of Biochemistry and Medical Genetics at the
University of Manitoba.
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Why do you think your work is highly cited?
Histone modifications (acetylation, phosphorylation, methylation,
ubiquitination) and the enzymes catalyzing these modifications are
key players in altering the structure and function of chromatin.
Histone acetyltransferases (HATs), histone deacetylases (HDACs),
histone kinases, histone phosphatases, and histone
methyltransferases mediate chromatin remodeling and are components
of a complex epigenetic network regulating gene expression during
development and differentiation. These processes are often
deregulated in cancer.
What are the circumstances which led you to your work?
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“Understanding the mechanisms by which oncoproteins and fusion proteins encoded by chromosomal translocations impact on chromatin structure and function has resulted in the discovery of new therapeutic strategies used in the treatment of cancer.”
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My interests in histone acetylation and chromatin
structure/function started as a graduate student in Peter Candido’s
lab at the University of British Columbia. During my graduate
studies Peter and I did a collaborative project with Ray Reeves
(University of British Columbia) to demonstrate that sodium
butyrate, which arrested cell cycling of cancer cells, was an HDAC
inhibitor. More recently, my research group purified and
characterized avian HDAC1 and demonstrated that several of the HDACs
were associated with the nuclear matrix. Our research attracted
several international collaborations in which we revealed the
mechanisms whereby HDACs are recruited by transcriptional
repressors. Also we were part of an international collaborative
effort to show that fusion proteins (e.g., AML-1-ETO) resulting from
translocation events occurring in cancer cells (e.g., acute myeloid
leukemia) inappropriately recruited HDACs to genes that should be
expressed, but that ended up being repressed.
A chromatin fractionation procedure, which was developed by my
research group to isolate transcriptionally active chromatin from
avian erythrocytes, was extremely informative in identifying the
role of histone modifications in chromatin remodeling and
transcription. Importantly, these studies allowed us to appreciate
the dynamics of histone modifications. These studies were initiated
when I was a post-doctoral fellow in Ken van Holde’s lab at Oregon
State University in collaboration with Harold Weintraub (Fred
Hutchinson Cancer Research Center). In Ken’s lab, the
post-doctoral fellows had freedom to explore multiple areas, with
one of my choices being chromatin structural and compositional
changes occurring in trout hepatocarcinoma. This interest led to
collaborative studies with Jim Wright (Manitoba Institute of Cell
Biology) and David Allis (University of Virginia) to demonstrate
that oncogene products impacting on the Ras-mitogen activated
protein kinase (MAPK) signal-transduction pathway increased the
steady state level of phosphorylated H1 and H3 histones in oncogene-transformed
cells. This collaborative effort provided the first direct evidence
that mitogen-induced phosphorylation of histone H3 was associated
with immediate-early genes, c-fos and c-myc.
How would you describe the significance of this work for your
field?
Alteration in expression of specific genes involved in growth
regulation can result in malignant transformation. Our work has
contributed to the increasing awareness of the role of chromatin
structure (epigenetics) in the regulation of gene expression and in
the genesis or suppression of cancer. The Ras-MAPK signaling pathway
is often constitutively active in different types of cancer (e.g.
breast, colon, melanoma), resulting in the activation of chromatin
modifying enzymes and the aberrant expression of genes.
Understanding the mechanisms by which oncoproteins and fusion
proteins encoded by chromosomal translocations impact on chromatin
structure and function has resulted in the discovery of new
therapeutic strategies used in the treatment of cancer. For example,
the realization that HDAC could be a therapeutic target provided the
incentive for investigators to develop HDAC inhibitors to treat
leukemia and other cancers.
Where do you see this research going 10 years from now?
The major objectives of my research are to understand the
molecular mechanisms regulating the location and activity of
chromatin-modifying enzymes, to determine the role of histone
modifications in altering chromatin structure and function, and to
investigate the nuclear substructure’s role in the organization
and function of chromatin and in providing diagnostic information in
the detection of cancer. These studies will reveal the mechanisms
regulating the sub-cellular trafficking and activity of the
chromatin-modifying enzymes and how these processes are deregulated
in disease states. Our attention will be on the role of signal
transduction pathways, the cytoskeleton and the nuclear
sub-structure in directing these chromatin remodeling processes. We
hope that our studies will lead to an appreciation of the impact of
multiple dynamic chromatin-modifying events at the level of
nucleosome structure and the oscillations in chromatin sub-domains.
Such knowledge will translate into new therapeutic approaches in the
treatment of diseases (cancer, heart disease) and the identification
of biomarkers in the early detection of cancer.
What lessons would you draw from your work to share with the
next generation of researchers?
I am convinced of the necessity to develop and be involved in
collaborative team research. Particularly rewarding are
collaborations that are cross-disciplinary and translational (that
is, clinical – basic research exchange). Be open-minded and do not
be concerned if your research views are not supported by others. If
your experimental plans are well controlled and research outcomes
are reproducible, then let your results judge your model.
| Dr. James Davie's
most-cited paper with 701 cites to date: |
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T. Heinzel et al., "A complex containing
N-COR, MSIN3 and histone deacetylase mediates transcriptional repression,"
(Nature 387[6628]: 43-8, 1 May 1997). |
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Source:
ISI
Essential Science Indicators |
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James R. Davie, Ph.D.
Manitoba Institute of Cell Biology
CancerCare Manitoba
University of Manitoba
Winnipeg, Manitoba, Canada
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cites
