Julie Secombe, Ph.D.

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 several 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 genetic variants 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 two systems. The first is the animal model Drosophila since it encodes a single, essential, KDM5 ortholog thereby overcoming the complication of functional redundancy among the four mammalian paralogs. In addition, we have recently begun human iPSCs to examine KDM5C function using organoids. 

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. 
• Developing a human iPSC model of KDM5C-intellectual disability (also known as Claes-Jensen syndrome). 

Follow me on twitter @flygirl2308

Yheskel, M., Hatch, H.A.M., Pedrosa, E., Terry, B. K., Siebels, A. A., Zheng, X.Y., Blok, L.E.R., Fencková, M., Sidoli, S., Schenck, A., Zheng, D., Lachman, H.M., and J. Secombe (2024). KDM5-mediated transcriptional activation of ribosomal protein genes alters translational efficiency to regulate mitochondrial metabolism in neurons. Nucleic Acids Research, 52 (11), 6201-6219. PMID:38597673

Rogers, M.F., Marshall, O.J., and J. Secombe (2023). KDM5-mediated activation of genes required for mitochondrial biology is necessary for viability in Drosophila. Development, doi.org/10.1242/dev.202024 PMID:37800333Schneider, B.K., Sun, S., Lee, M., Li, W., Skvir, N., Neretti, N., Vijg, J., and J. Secombe (2023) Expression of transposons contributes to aging in Drosophila. Genetics, DOI: 10.1093/genetics/iyad073

Yheskel, M., Sidoli, S., and J. Secombe (2023). Proximity labeling reveals a new in vivo network of interactors for the histone demethylase KDM5. Epigenetics & Chromatin 16(8) doi.org/10.1186/s13072-023-00481-y. PMID:36803422.

Belalcazar, H.M., Hendricks, E.L., Zamurrad, S., Liebl, F.L.W., and Secombe J (2021) The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction. Cell Reports, 34(7):108753. DOI:10.1016/j.celrep.2021.108753. PMID:33596422

Hatch, H.A.M., Belalcazar H.M., Marshall O.J., and Secombe J (2021) A KDM5-Prospero transcriptional axis functions during early neurodevelopment to regulate mushroom body formation. eLife doi.org/10.7554/elife.63886 PMID: 33729157

Hatch, H.A.M., O’Neill, M.H., Marion, R.W., Secombe, J.#., and L.H. Shulman# (2021) Caregiver-reported characteristics of children diagnosed with pathogenic variants in KDM5C. American Journal of Medical Genetics - Part A, doi:10.1002/amjg.a.62381 PMID:34089235
# co-corresponding authors.

Drelon, C., Belalcazar, H.M. and J. Secombe (2019) The histone demethylase KDM5 controls developmental timing by promoting prothoracic gland endocycles. Development, 146:dev182568 doi: 10.1242/dev.182568. PMID:31862793

Chen, K., Luan, X., Liu, Q., Wang, J., Chang X., 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 & Microbe 25, 1-16. PMID:30902578

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

Drelon, C., Belalcazar, H.M. and J. Secombe (2018) The histone demethylase KDM5 is essential for larval growth in Drosophila. Genetics. pii: genetics.301004.2018. doi: 10.1534/genetics.118.301004.

Navarro-Costa, P., McCarthy, A., Prudêncio, 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 remodeling. Nat. Comms., 10;7:12331. PMCID:PMC4987523.

Liu, X., and Secombe, J# (2015) KDM5 recognizes chromatin context to activate genes essential for mitochondrial function. Cell Reports, 13, 2219-2231.