My Omics Epic (a journey of learning, collaboration, innovation and technology) Thomas R. Sutter, Ph.D. Professor of Biology and Chemistry W. Harry Feinstone Chair of Excellence in Molecular Biology Research and Networking February 27, 2019 University of Memphis

Topics Omics in the Pre-Human Genome Era (April, 2003) Differential Hybridization (How sets of genes affect cell differentiation; cancer causation and prevention) Four people, $250,000, 3 years All things Omics (computational sciences and data integration) Microarray and Metabolomics Eight people, $50,000, 3 months (plus 2 years of data analysis!) Kennedy, L.H., Sutter, C.H., Carrion, S.L. Tran, Q.T., Bodreddigari, S., Kensicki, E., Mohney, R.P., and Sutter, T.R. 2013. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation. Toxicol. Sci. 132: 235-49. Sutter, C.H., Olesen, K.M., Bhuju, J., Guo, Z and Sutter, T.R. 2018. The AHR regulates metabolic reprogramming to promote SIRT1-dependent keratinocyte differentiation. J. Invest. Dermatology, in press [E-pub ahead of print], doi:10.1016/j.jid.2018.10.019. Targets for dioxin: genes for plasminogen activator inhibitor-2 and interleukin-1 beta TR Sutter, K Guzman, KM Dold, WF Greenlee Chemical Industry Institute of Toxicology, Research Triangle Park, NC Science  18 Oct 1991: Vol. 254, Issue 5030, pp. 415-418 DOI: 10.1126/science.1925598

Sensitive Scalable Comprehensive Central Dogma: Sensitive Scalable Comprehensive Proteomics Genomics - Component proteins/levels - Location, modifications, interactions - Function and activity - Structure (sequence) - Regulation - Function: expression in all of its forms This cartoon illustrates the classical pathway of ligand activated Aryl Hydrocarbon Receptor, AhR. AhR is classified as a member of the basic helix-loop-helix/Per-Arnt-Sim family of transcription factors. Normally in the cytoplasm, the Aryl hydrocarbon Receptor (AhR) is complexed with a dimer of Hsp90, hepatitis B virus X-associated protein 2 (XAP2) and p23 protein. TCDD, represented by the black circles, enters the cytoplasm and binds to AhR. It is believed that ligand binding causes a conformational change that exposes a NLS. Thus, ligand (TCDD) binding by the AhR results in the nuclear translocation of the complex, release of Hsp90 and other chaperone proteins, and dimerization with ARNT, which is the AhR Nuclear Translocator. (misnamed due to errata in findings of early experiment…name never changed) The newly formed TCDD/AhR/ARNT complex binds xenobiotic response elements (GCGTG) resulting in transactivation of specific xenobiotic responsive genes, such as CYP 1A1, 1B1, etc. The EC50 for induction of AhR-dependent gene expression by TCDD is ~6-10pM in mammalian cells. Despite this specific knowledge of the mechanism, it is still unclear how this relates to toxicity. Metagenomics (microbiome) Metabolomics - Community of microorganisms - Changes with state (e.g. disease) - Interaction with metabolome, epithelial barrier, immune system - Large scale small molecule - Metabolites: biochemistry - Flux: metabolism 3

Sutter Lab Collaborations at UM (30 omic publications) University of Memphis (6 dept) UTHSC (7 dept) Johns Hopkins University University of Pittsburgh Dartmouth Vanderbilt Fox Chase Cancer Center University of Nebraska NYU AHR research Nrf2 research NIH ES017014 (10) NIH CA39416 (15) GE (4) Roche Biosciences (3) Dow (3) NCI-N01-CN-95114 (3) University of Pennsylvania University of Dresden, Germany General Electric Metabolon Roche Bioscience, CA Roche, United Kingdom F. Hoffman-La Roche, Switzerland Dow Chemical NIH: NIEHS, NTP, NCI; NCTR, ORNL CYP1B1 research Other Total > $15M NIH ES08148 (5) MRC (4) DMAD-17-03-0229 (5) JHU CAAT (2) DOD BC022345 (4) NIH U01AA13515 (5)

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