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Charles Danko, Ph.D.

Assistant Professor of Biomedical Sciences

Genes are the basic blueprints for all living things, but how are those blueprints interpreted and turned into living, breathing organisms? That’s the question Dr. Charles Danko pursues in his work. Although the DNA tucked inside every cell provides a neat code for that cell to read and translate into RNA (ribonucleic acid) and proteins, the way those blueprint instructions are put into action often decides the difference between health and disease. In his studies, Danko is looking beyond simple linear sequences of genes and into the complex ways cells turn those instructions into action, in a process called gene regulation.

Breast cancer is one disease where gene regulation plays a big role, and it strikes humans as well as dogs and cats at alarming rates. In humans, roughly 70% of breast cancer cases are estrogen receptor positive, meaning that the gene encoding the estrogen receptor alpha is “turned on” in those cells, a trait that may well be key to their ability to multiply almost endlessly. Danko is working to develop ways of analyzing the genome of breast cancer cells to quickly determine which genes are activated and therefore which drugs might be the best choices for treating that individual cancer patient. The current methods for accomplishing this analysis are laborious and require ten or more assays to accomplish. Danko thinks with a single assay and computational technologies that he’s developing for finding patterns in the data, he can accomplish the same goal quickly and efficiently. The work has the potential to help many animals and humans suffering from cancer of the breast and other tissues.

A heart disease called arrhythmogenic right ventricular cardiomyopathy (ARVC) strikes in both humans and in purebred boxers, a coincidence that could eventually help both humans and dogs overcome the condition. Danko is mapping the genome of affected and unaffected dogs to identify the genes responsible for ARVC and to unearth how those genes cause the disease to develop. Knowing the genetic basis of the disease will help breeders eliminate it from breeding lines and could eventually help develop drugs to treat the ARVC in humans.

Evolution is another phenomenon that has its roots in gene regulation, where subtle differences in sequences can mean big differences in an animal. The differences between humans and chimps, for instance, are obvious and profound, but the protein-coding sequences of the two species are 99% identical. Danko thinks differences in gene regulation (i.e., in which the expression of genes is “turned on” or “turned off”) contribute to these evolutionary differences. In other words, it’s not the subtle sequence differences in genes and proteins that make a species, it’s the big effects those tiny changes have on the relative rates at which genes are regulated and turned into proteins that can make a species distinct. To understand this process, Danko is analyzing DNA sequences and genome function using a technique called GRO-seq to compare the genomes of humans and primates and see how regulatory elements differ between species. His early results show that regions that control gene expression, in which humans and primates differ, show signs of adaptive evolution, indicating that evolving new ways of regulating genes has actually helped humans and chimps adapt to their own particular lifestyle. This result offers support to his idea that gene regulation plays a big role in how evolution creates differences between related animals.

In a somewhat related vein, Danko is collaborating with Dr. Avery August of the College of Veterinary Medicine on a project to study the process of evolution on a smaller scale, in T-cells, a particular kind of immune system cell. As they mature, T-cells acquire different types of abilities and roles in the body, but they all maintain exactly the same genome. Danko is studying this maturation process, and he’s interested in its importance for immunology, but he’s also thinking about the process as a model for how development is controlled by gene regulation, creating apparent diversity from cells that are genetically identical.


Publications:

  1. Core LJ, Martins AL, Danko CG, Waters CT, Siepel A, Lis JT. Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nature Genetics. 46, 1311–1320. Abstract. Featured in NG News and Views.

  2. Luo X, Chae M, Krishnakumar R, Danko CG, Kraus WL. (2014) Dynamic reorganization of the AC16 cardiomyocyte transcriptome in response to TNFalpha signaling revealed by integrated genomic analyses. BMC Genomics. Feb 24;15(1):155.
     
  3. Oxford EM, Danko CG, Fox PR, Kornreich BG, Moïse NS. (2014) Change in ß-Catenin Localization Suggests Involvement of the Canonical Wnt Pathway in Boxer Dogs with Arrhythmogenic Right Ventricular Cardiomyopathy. Journal of Veterinary Internal Medicine. Jan;28(1):92-101. Abstract.

  4. Hah N, Murakami S, Nagari A, Danko CG, Kraus WL. (2013) Enhancer Transcripts Mark Active Estrogen Receptor Binding Sites. Genome Research. May 1.

  5. Zeng L, Sang Chul C, Danko CG, Siepel A, Stanhope MJ, Burne RA. (2013) Gene Regulation by CcpA and Catabolite Repression Explored by RNA-Seq in Streptococcus mutans. PLoS ONE. 8(3).

  6. Danko CG, Hah N, Luo X, Martins AL, Core L, Lis JT, Siepel A, Kraus WL. (2013) Signaling Pathways Differentially Affect RNA Polymerase II Initiation, Pausing, and Elongation Rate in Cells. Molecular Cell. Jun 6;50(5):778. Abstract. Cover Article. Featured in a perspective piece. Recommended by F1000.

  7. Gronau I, Hubisz MJ, Gulko B, Danko CG, Siepel A. (2011) Bayesian inference of ancient human demography from individual genome sequences. Nature Genetics.  Sep 18;43(10):1031-4. Abstract.

  8. Oxford EM, Danko CG, Kornreich BG, Maass K, Hemsley SA, Raskolnikov D, Fox PR, Delmar M, Moïse NS. (2011) Ultrastructural changes in cardiac myocytes from Boxer dogs with arrhythmogenic right ventricular cardiomyopathy. Journal of Veterinary Cardiology. Jun;13(2):101-13. Cover Article. Abstract.

  9. Hah N, Danko CG, Core L, Waterfall JJ, Siepel A, Lis JT, Kraus WL. (2011) A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. Cell. May 13;145(4):622-34. Abstract.  Featured in a perspective piece.

  10. Schuster SC, Miller W, Ratan A, Tomsho LP, Giardine B, Kasson LR, Harris RS, Petersen DC, Zhao F, Qi J, Alkan C, Kidd JM, Sun Y, Drautz DI, Bouffard P, Muzny DM, Reid JG, Nazareth LV, Wang Q, Burhans R, Riemer C, Wittekindt NE, Moorjani P, Tindall EA, Danko CG, Teo WS, Buboltz AM, Zhang Z, Ma Q, Oosthuysen A, Steenkamp AW, Oostuisen H, Venter P, Gajewski J, Zhang Y, Pugh BF, Makova KD, Nekrutenko A, Mardis ER, Patterson N, Pringle TH, Chiaromonte F, Mullikin JC, Eichler EE, Hardison RC, Gibbs RA, Harkins TT, Hayes VM. (2010) Complete Khoisan and Bantu genomes from southern Africa. Nature. Feb 18;463(7283):943-7. Cover Article. Abstract.

  11. Danko CG, Pertsov AM. Identification of gene co-regulatory modules and associated cis-elements involved in degenerative heart disease. BMC Medical Genomics. 2009 May 28;2:31

  12. Danko CG, McIlvain VA, Qin M, Knox BE, Pertsov AM. (2007) Bioinformatic identification of novel putative photoreceptor specific cis-elements. BMC Bioinformatics. Oct 22;8:407.

  13. Jarrar MH, Danko CG, Reddy S, Lee YJ, Bibat G, Kaufmann WE. (2003) MeCP2 expression in human cerebral cortex and lymphoid cells: immunochemical characterization of a novel higher-molecular-weight form. Journal of Child Neurology. Oct;18(10):675-82. Abstract.