Assistant Professor, Department of Genetics
We are interested in understanding the molecular mechanisms that govern Myc transcription factor function during development. In mammalian cells, N- and c-Myc are essential for normal cell function but are potent oncogenes when deregulated. Although Myc proteins are relatively weak transcriptional activators, they regulate a surprisingly large number of genes (~15% of genomic loci) and broadly affect gene expression patterns. This is reflected in Myc’s ability to affect diverse cellular processes including growth, cell cycle progression, apoptosis and fate specification.
We have carried out a genetic screen to identify novel effectors and regulators of Myc-induced cell growth in vivo using the genetically amenable model organism Drosophila melanogaster. Using an eye phenotype caused by dMyc overexpression, we have identified 41 genomic regions that affect dMyc’s ability to induce cell growth. One gene that we identified as being required for dMyc function is the histone demethylase Little Imaginal Discs (Lid). Regulated methylation of lysine residues within histone proteins has been shown to influence crucial cellular functions including the gene expression programs essential to stem cell maintenance and cellular differentiation. Our finding that a histone demethylase is required for dMyc function is therefore of particular interest and we are currently identifying additional components of the Lid-dMyc complex and determining the molecular function of this (and other) Lid complexes in vivo. We are also identifying and characterizing the remaining genes identified in our screen and determining how they function to regulate dMyc-dependent cell growth.
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, in press.
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Albert Einstein College of Medicine
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