Faculty Profile

Dr. Julie Secombe, Ph.D.

Julie Secombe, Ph.D.

Associate Professor, Department of Genetics

Associate Professor, Dominick P. Purpura Department of Neuroscience

Areas of Research: Chromatin and gene expression; KDM5 histone demethylase-regulated transcription; KDM5-mediated intellectual disability; Myc oncogene-induced growth and genome instability; Linking Myc to activation of transposons and aging.

Professional Interests

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 KDM5A, KDM5B and 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:

  • Examining neuronal phenotypes of kdm5 mutant animals and identifying KDM5 target genes to gain insight into how loss of human KDM5 genes result in intellectual disability. 
  • Generating and characterizing the phentoypes and gene expression changes in fly strains harboring mutations that are analogous to those found in intellectual disability patients. Significantly, all missense mutations in KDM5 genes found in affected patients occur in evolutionarily conserved residues.
  • Defining KDM5 target genes in larvae and in adults and defining the different mechanisms used by KDM5 to activate and repress gene expression. 
  • Determining how KDM5 acts with the oncoprotein Myc to regulate cell growth, as this is likely to be directly relevant to understanding how KDM5A/B causes cancer in humans.

 

Selected Publications

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, 13:2219-2231.

Navarro-Costa, P., McCarthy, A., Prudencio, P., Greer, C., Guilgur, L.G., Becker, J., Secombe, J., Rangan, P and R. Martinho (2016) Early programming of the oocyte epigenome temporally controls late prophase I transcription and chromatin remodelling. Nat. Comms. 10;7:12331.

Zamurrad, S., Hatch, H.A.M., Drelon, C., Belalcazar, H.M, and J.Secombe (2018) A Drosophilamodel of intellectual disability caused by mutations in the histone demethylase KDM5. Cell Reports 22, 2359-2369.  PMCID:PMC5854480.

Drelon, C., Belalcazar, H.M. and J. Secombe (2018) The histone demethylase KDM5 is essential for larval growth in DrosophilaGenetics, 209, 773-787. PMCID:PMC6028249

Chen, K., Luan, X., Liu, Q., Wang, J., ChangX., Snijders A. M., Mao J-H., Secombe J., Dan Z, Chen J-H., Wang Z., Dong X., Qiu C., Chang X., Zhang D., Celniker S. E., and Xingyin Liu (2019) Drosophila KDM5 regulates social behavior through immune control and gut microbiota maintenance. Cell Host & Microbe25, 1-16. PMID:30902578

Drelon, C., Belalcazar H.M., and J. Secombe (2019) The histone demethylase KDM5 controls developmental timing by promoting prothoracic gland endocycles. https://www.biorxiv.org/content/10.1101/617985v2

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Research Information