In my lab, we define the functional role of epigenetics in transcriptional regulation of head and neck squamous cell carcinoma (HNSCC) progression. To evaluate the whole-genome distribution of various histone marks, we are using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) methodology for primary tissues recently developed in my lab. My research group was the first to demonstrate the cancer-specific distribution of H3K4me3 and H3K27ac marks and their role in cancer-related gene expression in HNSCC. The research of my team showed that an aberrant chromatin alteration is a central event in carcinogenesis, and the therapeutic control of chromatin structure can prevent the primary of secondary cancerization. Furthermore, our preliminary data further suggest that the differential enrichment of these disease-specific histone marks and DNA methylation correlate with alternative splicing events (ASE) formation. For this project, we employed a novel bioinformatical tool for the detection of cancer-specific ASEs. Through thorough functional validation of the individual ASEs, we demonstrated that each of them has a unique mechanism of malignant transformation of the cells. Due to high disease-specificity, ASEs represent the perfect biomarkers and the neoantigens that have direct application to clinical practice.
Technology Expertise Keywords
HNSCC, ChIP-Seq, RNA-Seq, chromatin, transcription, alternative splicing
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Kelley DZ, Flam EL, Izumchenko E, Danilova LV, Wulf HA, Guo T, Singman DA, Bahman A, Skaist A, Considine M, Welch JA, Stavrovskaya E, Bishop JA, Westra WH, Khan Z, Koch WM, Sidransky D, Wheelan S, Favorov AV, Califano JA, Fertig EJ*, Gaykalova DA*. Integrated analysis of whole-genome ChIP-Seq and RNA-Sequencing data of primary head and neck tumor samples associates HPV integration sites with open chromatin marks. Cancer Res. 2017 Sep 25. pii: canres.0833.2017. doi: 10.1158/0008-5472.CAN-17-0833. [Epub ahead of print]. PMID: 28947419.*Equal Contribution.
Guo T, Sakai A, Afsari B, Considine M, Danilova L, Favorov AV, Kelley DZ, Flam EL, Khan Z, Wheelan S, Gutkind S, Fertig EJ*, Gaykalova DA*, Califano JA*. Definition of Alternative Splice Expression in HPV-related oropharyngeal cancer includes a novel functional splice variant of AKT3. Cancer Res. 2017 Oct 1;77(19):5248-5258. doi: 10.1158/0008-5472.CAN-16-3106. Epub 2017 Jul 21. PMID: 28733453. *Equal contribution
Faraji F, Zaidi M, Fakhry C, Gaykalova DA. Molecular Mechanisms of Human Papillomavirus-Related Carcinogenesis in Head and Neck Cancer. Microbes Infect. 2017 Sep - Oct;19(9-10):464-475. doi: 10.1016/j.micinf.2017.06.001. Epub 2017 Jun 12. PMID: 28619685
Kagohara LT†, Stein-O’Brien G†, Kelley DZ, Flam EL, Wick H, Danilova LV, Easwaran H, Favorov AV, Qian J, Gaykalova DA*, and Fertig EJ*. Epigenetic Regulation of Gene Expression in Cancer: Techniques, Resources, and Analysis. Brief Funct Genomics. 2017 Aug 11. doi: 10.1093/bfgp/elx018. [Epub ahead of print]. PMID: 28968850. †*Equal Contribution.
Gaykalova DA*, Zizkova V, Guo T, Tiscareno I, Wei Y, Vatapalli R, Hennessey PT, Ahn J, Danilova L, Khan Z, Bishop JA, Gutkind JS, Koch WM, Westra WH, Fertig EJ, Ochs MF, Califano JA*. Integrative computational analysis of transcriptional and epigenetic alterations implicates DTX1 as a putative tumor suppressor gene in HNSCC. Oncotarget. 2017 Feb 28;8(9):15349-15363. doi: 10.18632/oncotarget.14856. PMID: 28146432. *Corresponding authors
Hypermethylated Gene Markers for Head and Neck Cancer
Patent # 14/381,489
We have detected the panel of differentially methylated genes in head and neck cancers, which can be used as disease biomarkers
Methods and Agent for Modulating the RNA Polymerase II-Histone Surface
Patent # 12/952,295
We have described the RNA Polymerase II-Histone surface interactions and methods/agents that can modulate them