Assistant Adjunct Professor of Biochemistry, Biophysics and Structural Biology*
*and Affiliate in Division of Cell and Developmental Biology, and Scientific Director of the Innovative Genomics Initiative (IGI)
The Corn Lab develops and uses next-generation genome editing and regulation technologies to enable fundamental biological discoveries and develop potential therapies for human genetic diseases. We focus on the mechanisms by which cells repair their DNA and use ubiquitin signaling to propagate cellular signals. Through technology development, mechanistic cellular biochemistry, and translational projects, we are working to unravel complex cellular phenotypes to further biological understanding and improve human health.
Cells must maintain the integrity of their genomes or risk permanent damage to functional sequences. Eukaryotes have evolved a wide variety of integrated pathways to sense and repair multiple types of DNA damage, from bulky lesions to double strand breaks. Deficiencies in these pathways can cause cells to accumulate genomic errors that lead to human diseases, including somatic cancers and Mendelian inherited genetic disorders. Harnessing DNA repair through the development of programmable nucleases such as ZFNs, TALENs, and recently CRISPR-Cas effectors is revolutionizing approaches to fundamental biological discovery and holds great promise for the cure of genetic diseases.
Next-generation gene editing tools, exemplified by CRISPR-Cas effectors such as Cas9, are fundamentally DNA damaging agents that introduce double strand breaks (or nicks if so engineered). Hence, they are inextricably linked to DNA repair in that they represent new opportunities to study DNA repair in human cells and intensify the urgency of studying these processes.
Research in the Corn lab seeks to understand the intersection between human DNA repair and genome editing tools and to develop new approaches to cure human diseases using genome editing. We furthermore use advanced genome editing to uncover the mechanisms by which cells use ubiquitin-based signals to encode information, including the stimulus-dependent destruction of entire organelles. We take a multidisciplinary approach to tackle these problems that includes computational modeling, in vitro biochemistry and biophysics, genome-wide screening, and mechanistic cellular biochemistry.
The intersection of DNA repair and genome editing
The development of CRISPR-Cas9 for genome editing and regulation is transforming biological research and has opened up potential therapeutic avenues. However there are still many problems that we lack the tools to tackle. For example, while Cas9 can be used to "knock out" genes through error-prone sequence disruption, methods to precisely insert or replace sequences are still in their infancy. Gene editing outcomes are currently unpredictable in part because we have fundamental gaps in our understanding of DNA repair. As a programmable nuclease, CRISPR-Cas9 represents both a powerful tool to edit the genome through the controlled introduction of DNA damage, and also an exciting new opportunity to study the ways in which human cells keep their genomes intact. We are working to determine the molecular mechanisms by which cells process DNA damage, such as that which is incurred during genome editing, with the goal of furthering fundamental understanding of DNA repair and finding routes to high efficiency gene correction.
Using genome editing to decipher ubiquitin signals
The attachment and removal of ubiquitin from substrate proteins can encode a wide range of signals, controlling cellular phenotypes from cell division to organelle abundance. But the complex genetics and many players involved in ubiquitin signaling have made it slow and difficult to decipher these functional networks. We are using next-generation genome editing and regulation technologies to gain molecular insight into ubiquitin-mediated signaling cascades involved in cellular homeostasis. For example, using unbiased screens with complex phenotypes, we are uncovering novel ubiquitin-related effectors that regulate processes such as human DNA repair and organelle autophagy. Endogenous tagging and editing approaches enable us to gain a deep understanding of the mechanisms by which these effectors encode and decode ubiquitin-mediated signals.
Translational impact in the real world
Genome editing holds great promise to uncover the root causes of human diseases and even to reverse mutations that cause inherited genetic disorders. We collaborate with clinicians and industry groups to translate genome editing approaches towards real world applications. Working with therapeutic companies, we use CRISPR screening technologies in challenging contexts to identify and validate druggable targets in emerging therapeutic areas. We have recently determined how certain cancer cells resist cutting-edge targeted oncology therapies and are developing strategies to bring them back under control. We also use genome editing to explore the mechanisms by which genomic variation causes or modifies disease, for example by introducing disease-associated noncoding SNPs into human cells. Finally, we develop reagents aimed at curing genetic disorders via precision sequence replacement, for example by correcting the sickle cell disease mutation in human hematopoietic stem cells.
Baltimore D, Berg P, Botchan M, Carroll D, Charo RA, Church G, Corn JE, Daley GQ, Doudna JA, Fenner M, Greely HT, Jinek M, Martin GS, Penhoet E, Puck J, Sternberg SH, Weissman JS, and Yamamoto KR. (2015) A prudent path forward for genomic engineering and germline gene modification. Science, 348:36-8.
Cunningham CN, Baughman JM, Phu L, Tea J, Yu C, Coons M, Kirkpatrick DS, Bingol B*, and Corn JE*. (2015) USP30 and Parkin homestatically regulate ubiquitin chain abundance on mitochondria. Nature Cell Biology, 17:160-9. *co-corresponding
Corn JE* and Vucic D*. Ubiquitin in inflammation: the right linkage makes all the difference. (2014) Nature Structural and Molecular Biology, 21:297-300. *co-corresponding
Phillips AH*, Zhang Y*, Cunningham CN, Zhou L, Forrest WF, Liu PS, Steffek M, Lee J, Tam C, Helgason E, Murray JM, Kirkpatrick DS, Fairbrother WJ, Corn JE. (2013) The timescale of conformational dynamics controls ubiquitin-deubiquitinase interactions and influences ubiquitin signaling in vivo. PNAS, 110:11379-84. *equal contribution
Zhang Y, Zhou L, Rouge L, Phillips AH, Lam C, Liu P, Sandoval W, Helgason E, Murray J, Wertz IE, Corn JE. (2013) Conformational stabilization of ubiquitin yields potent and selective inhibitors of USP7. Nature Chemical Biology, 9:51-8. See also News and Views: doi:10.1038/nchembio.1143
Fleishman SJ, Corn JE, Strauch EM, Whitehead TA, Karanicolas J, Baker D. (2011) Hotspot-centric de novo design of protein binders. J Mol Biol, 413:1047-62. Bentley ML, Corn JE, Dong KC, Phung Q, Cheung TK, Cochran AG. (2011) Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex. EMBO J, 30:3285-97.
Fleishman SJ, Leaver-Fay A, Corn JE, Strauch EM, Khare SD, Koga N, Ashworth J, Murphy P, Richter F, Lemmon G, Meiler J, Baker D. (2011) RosettaScripts: a scripting language interface to the Rosetta macromolecular modeling suite. PLoS One, 6:e20161.
Fleishman SJ*, Whitehead TA*, Ekiert DC*, Dreyfus C, Corn JE, Strauch E-M, Wilson IA, and Baker D. (2011) Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. Science, 332:816-21. *equal contribution.
Karanicolas J*, Corn JE*, Chen I*, Joachimiak LA*, Dym O, Chung S, Albeck S, Unger T, Hu W, Liu G, Delbecq S, Montelione G, Spiegel C, Liu D, and Baker D. (2011) A de novo protein binding pair by computational design and directed evolution. Molecular Cell, 42:250-60. *equal contribution.
Photo credit: Mark Hanson at Mark Joseph Studios.
Last Updated 2016-10-04