My lab has a long-term interest in understanding the function of the KDM5 family of transcriptional regulators. KDM5 proteins have a unique combination of chromatin modifying and recognition domains that are likely to regulate gene expression through distinct mechanisms. In addition, an ever-growing body of evidence links their dysregulation to human pathologies. Of the four human KDM5 paralogs (KDM5A-D), three are clinically significant. KDM5A or KDM5B are overexpressed in a large number of cancers, and loss of function mutations in KDM5C are found in patients with X-linked intellectual disability.
To-date, however, no effective therapies exist to treat disorders caused by KDM5 protein dysfunction, primarily because we do not have a comprehensive knowledge of KDM5 target genes, nor of the mechanisms by which KDM5 proteins regulate gene expression. To dissect KDM5 function we use Drosophila since it encodes a single, essential, KDM5 ortholog thereby overcoming the complication of functional redundancy among the four mammalian paralogs.
We currently have a number of projects going on in the lab:
Secombe, J., Pierce, S.B and R.N. Eisenman. (2004) Myc: A weapon of Mass destruction. Cell, 117:153-156
Brumby, A*., J Secombe*,J. Horsfield, M. Coombe, N. Amin, D. Coates, R. Saint and H. Richardson (2004) A genetic screen for dominant suppressors of a cyclin E hypomorphic mutation identifies novel regulators of S phase entry. Genetics 168:227-251 *Co-first authors.
Loo, L*., J. Secombe*, J.T. Little, L. Carlos, C. Yost, P-F Cheng, E.M. Flynn, B.A. Edgar and R.N. Eisenman. (2005) The transcriptional repressor dMnt is a regulator of growth and lifespan in Drosophila. Mol Cell Biol. 25:7078-91 *Co-first authors.
Secombe, J. and R.N. Eisenman (2007) The function and regulation of the JARID1 family of histone H3 lysine 4 demethylases: the Myc connection. Cell Cycle 6:1324-8
Secombe, J., L. Li, L. Carlos and R.N. Eisenman (2007) The Trithorax protein Lid is a trimethyl H3-K4 demethylase required for dMyc-induced growth. Genes Dev. 21:537-551
Grzeschik N.A., N. Amin, J. Secombe, A.M. Brumby and H. E. Richardson (2007) Abnormalities in cell proliferation and apico-basal cell polarity are separable in Drosophila lgl mutant clones in the developing eye. Dev. Biol. 311:106-23
Li, L., C. Greer, R.N. Eisenman and J. Secombe (2010) Essential functions of the histone demethylase Lid. PLoS Genetics 6(11):e1001221.
DiTacchio, L., Le, HD., Vollmers, C., Hatori, M., Witcher, M., Secombe, J. and Panda, P. (2011) Histone lysine demethylase JARID1a activates transcription regulators CLOCK-BMAL1 and influences the circadian clock. Science, 333:1881-1884.
Greer, C., Lee, M., Westerhof, M., Milholland, B., Spokony, R., Vijg, J. and Secombe, J (2013) Myc-dependent genome instability and lifespan in Drosophila. PLoS ONE, 8(9): e74641.
Li, L., Anderson, S., Secombe, J and R.N. Eisenman (2013) The Drosophila ubiquitin-specific protease Puffyeye regulates dMyc-mediated growth. Development, 140:1-12.
Liu, X., Greer, C., and J. Secombe (2014) KDM5 interacts with Foxo to modulate cellular levels of oxidative stress. PLos Genetics 10(10): e1004676
Liu, X., and J. Secombe (2015) The histone demethylase KDM5 activates gene expression by recognizign chromatin context through its PHD reader motif. Cell Reports, in press.
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