Credentials: High-throughput functional genomics to investigate DNA repair and pathogenic effectors
Position title: Assistant Professor
Wisconsin Institutes for Medical Research (WIMR) west wedge
1111 Highland Avenue
Madison, WI 53705
High-Throughput Functional Genomics To Investigate DNA Repair And Pathogenic Effectors
With the emerging appreciation of precision medicine, the link of genetic and epigenetic perturbations to their phenotypes is vital. With the advent of CRISPR-mediated genome editing and high-throughput sequencing, we can both systematically perturb the genome and quantitatively measure their phenotypic effects. In the Hess lab, we are broadly interested in both the development and application of these and other functional genomics technologies to address critical biological questions and improve human health.
Investigating the regulation of DNA repair
Mutations in DNA repair associated genes have been implicated in many diseases, including cancer and neurodegeneration. Many chemotherapies use DNA damaging agents to induce cytotoxicity, and DNA repair deficiency-causing mutations can serve as biomarkers for response and resistance to these treatments. Furthermore, in the genome-editing field, there is growing interest in manipulating these DNA repair pathways to improve the efficiency and fidelity of editing. Therefore, annotating and understanding the effect of genes, variants, and recruited proteins on DNA repair is essential. We employ genetic screening methods with an array of phenotypic readouts (drug selection, fluorescent reporters, high-throughput sequencing, etc.) to quantify the effects of these genetic perturbations. We use these findings to dissect the molecular mechanisms that regulate DNA repair and translate these findings to improve genome editing and understand differential responses to cancer therapies.
Characterization of pathogenic effectors
Microbial and viral pathogens have a significant impact on global human health. These pathogens have evolved efficient methods to survive and proliferate in mammalian hosts by manipulating endogenous machinery. In some cancers, these alterations have an oncogenic role, either promoting tumor growth or developing drug resistance. Effector proteins from the pathogen often drive the efficient manipulation of the host. With current efforts to mine microbial and viral genomes, the list of potential effectors is ever-growing, so the development of tools to systematically characterize these effectors is critical. In the Hess lab, we dissect how these effectors hijack the host machinery using high-throughput functional genomics. In particular, we are focused on effectors that can modulate DNA repair, epigenetic states, and immune response. These findings will uncover new host-pathogen interactions and novel therapeutic strategies and targets.
Functional Genomics Technology Development
In the Hess lab, we develop high-throughput screening technologies to answer critical questions in biology and health. We have expertise with CRISPR/Cas genetic screening tools (CRISPR cutting/knockout, CRISPRi/a, base editing, and prime editing) and screening protein libraries in a mammalian cellular context. We are interested in improving these technologies, including library construction, novel genome-editing tools, and high-throughput selection strategies. In addition to our interests in DNA repair and pathogenic effectors, we are excited to apply these technologies to a broad set of questions.
Perform a customized PubMed literature search for Gaelen Hess
- Wisnovsky, S., L. Möckl, S.A. Malaker, K. Pedram, G.T. Hess, N.M. Riley, M.A. Gray, B.A.H. Smith, M.C. Bassik, W.E. Moerner, and C.R. Bertozzi. (2021). Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7. Proceedings of the National Academy of Sciences of the United States of America, 118: .
- Tycko, J., N. DelRosso, G.T. Hess, . Aradhana, A. Banerjee, A. Mukund, M.V. Van, B.K. Ego, D. Yao, K. Spees, P. Suzuki, G.K. Marinov, A. Kundaje, M.C. Bassik, and L. Bintu. (2020). High-Throughput Discovery and Characterization of Human Transcriptional Effectors. Cell, 183: 2020-2035.e16.
- Lahey, L.J., R.E. Mardjuki, X. Wen, G.T. Hess, C. Ritchie, J.A. Carozza, V. Böhnert, M. Maduke, M.C. Bassik, and L. Li. (2020). LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP. Molecular cell, 80: 578-591.e5.
- Debets, M.F., O.Y. Tastan, S.P. Wisnovsky, S.A. Malaker, N. Angelis, L.K.R. Moeckl, J. Choi, H. Flynn, L.J.S. Wagner, G. Bineva-Todd, A. Antonopoulos, A. Cioce, W.M. Browne, Z. Li, D.C. Briggs, H.L. Douglas, G.T. Hess, A.J. Agbay, C. Roustan, S. Kjaer, S.M. Haslam, A.P. Snijders, M.C. Bassik, W.E. Moerner, V.S.W. Li, C.R. Bertozzi, and B. Schumann. (2020). Metabolic precision labeling enables selective probing of O-linked N-acetylgalactosamine glycosylation. Proceedings of the National Academy of Sciences of the United States of America, 117: 25293-25301.
- Ferraro, N.M., B.J. Strober, J. Einson, N.S. Abell, F. Aguet, A.N. Barbeira, M. Brandt, M. Bucan, S.E. Castel, J.R. Davis, E. Greenwald, G.T. Hess, A.T. Hilliard, R.L. Kember, B. Kotis, Y. Park, G. Peloso, S. Ramdas, A.J. Scott, C. Smail, E.K. Tsang, S.M. Zekavat, M. Ziosi, . Aradhana, . , K.G. Ardlie, T.L. Assimes, M.C. Bassik, C.D. Brown, A. Correa, I. Hall, H.K. Im, X. Li, P. Natarajan, . , T. Lappalainen, P. Mohammadi, S.B. Montgomery, and A. Battle. (2020). Transcriptomic signatures across human tissues identify functional rare genetic variation. Science (New York, N.Y.), 369: .
- Morgens, D.W., C. Chan, A.J. Kane, N.R. Weir, A. Li, M.M. Dubreuil, C.K. Tsui, G.T. Hess, A. Lavertu, K. Han, N. Polyakov, J. Zhou, E.L. Handy, P. Alabi, A. Dombroski, D. Yao, R.B. Altman, J.K. Sello, V. Denic, and M.C. Bassik. (2019). Retro-2 protects cells from ricin toxicity by inhibiting ASNA1-mediated ER targeting and insertion of tail-anchored proteins. eLife, 8: .
- Tycko, J., M. Wainberg, G.K. Marinov, O. Ursu, G.T. Hess, B.K. Ego, . Aradhana, A. Li, A. Truong, A.E. Trevino, K. Spees, D. Yao, I.M. Kaplow, P.G. Greenside, D.W. Morgens, D.H. Phanstiel, M.P. Snyder, L. Bintu, W.J. Greenleaf, A. Kundaje, and M.C. Bassik. (2019). Mitigation of off-target toxicity in CRISPR-Cas9 screens for essential non-coding elements. Nature communications, 10: 4063.
- Ritchie, C., A.F. Cordova, G.T. Hess, M.C. Bassik, and L. Li. (2019). SLC19A1 Is an Importer of the Immunotransmitter cGAMP. Molecular cell, 75: 372-381.e5.
- Breslow, D.K., S. Hoogendoorn, A.R. Kopp, D.W. Morgens, B.K. Vu, M.C. Kennedy, K. Han, A. Li, G.T. Hess, M.C. Bassik, J.K. Chen, and M.V. Nachury. (2018). A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies. Nature genetics, 50: 460-471.
- Li, X., Y. Kim, E.K. Tsang, J.R. Davis, F.N. Damani, C. Chiang, G.T. Hess, Z. Zappala, B.J. Strober, A.J. Scott, A. Li, A. Ganna, M.C. Bassik, J.D. Merker, . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , . , I.M. Hall, A. Battle, and S.B. Montgomery. (2017). The impact of rare variation on gene expression across tissues. Nature, 550: 239-243.