Description of Research Expertise

While we conventionally think of genomic DNA as a simple polymer of A's, C's, G's, and T's, the chemistry of the genome is in fact far more interesting.

Our laboratory focuses on the DNA modifying enzymes that provide an added layer of complexity to the genome. These enzymes can be involved in the purposeful introduction of mutations or in the chemical modification of nucleobases, making DNA into a remarkably dynamic entity. Many of these processes are at the heart of the battle between the immune system and pathogens or are central to epigenetics.

* Our work can be broadly classified in two areas:

* Enzymatic deamination, oxidation and methylation of cytosine bases, with a focus on AID/APOBEC DNA deaminases and TET oxygenases

* Targeting Pathogen Pathways that Promote Evolution and Antibiotic Resistance, with a focus on the LexA/RecA axis governing the bacterial SOS response.

* We utilize a broad array of approaches, which include 1) biochemical characterization of enzyme mechanisms, 2) chemical synthesis of enzyme probes, and 3) biological assays spanning bacteriology, immunology, and virology to study DNA modifying enzymes and pro-mutagenic pathways.

* Our research program aims to understand diversity generating enzymes and pathways in vitro, to perturb their function in physiological settings, and to harness the biotechnological potential of these diversity-generating pathways.

Selected Publications

Schutsky EK, DeNizio JE, Hu P, Liu MY, Nabel CS, Fabyanic EB, Hwang Y, Bushman FD, Wu H, Kohli RM: Nondestructive, base-resolution sequencing of 5-hydroxymethylcytosine using a DNA deaminase Nature Biotech 36 : 1083–1090,2018.

DeNizio JE, Liu MY, Leddin EM, Cisneros GA, Kohli RM: Selectivity and Promiscuity in TET-Mediated Oxidation of 5-Methylcytosine in DNA and RNA Biochemistry 58 : 411-421,2019.

Samuels AN, Roggiani M, Zhu J, Goulian M, Kohli RM: The SOS Response Mediates Sustained Colonization of the Mammalian Gut Infect Immun 87 : pii: e00711-18,2019.

Ghanty U, DeNizio JE, Liu MY, Kohli RM: Exploiting Substrate Promiscuity to Develop Activity-Based Probes for TET Family Enzymes J Am Chem Soc 140 (50): 17329-17332 ,2018.

Selwood T, Larsen BJ, Mo CY, Culyba MJ, Hostetler ZM, Kohli RM, Reitz AB, Baugh SDP.: Advancement of the 5-Amino-1-(Carbamoylmethyl)-1H-1,2,3-Triazole-4-Carboxamide Scaffold to Disarm the Bacterial SOS Response. Front Microbiol 9 : 2961,2018.

Hrit J, Goodrich L, Li C, Wang BA, Nie J, Cui X, Martin EA, Simental E, Fernandez J, Liu MY, Nery JR, Castanon R, Kohli RM, Tretyakova N, He C, Ecker JR, Goll M, Panning B: OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development Elife 7 : pii: e34870,2018.

Hostetler ZM, Ferrie JJ, Bornstein MR, Sungwienwong I, Petersson EJ, Kohli RM: Systematic Evaluation of Soluble Protein Expression Using a Fluorescent Unnatural Amino Acid Reveals No Reliable Predictors of Tolerability ACS Chem Bio 13 (10): 2855-2861,2018.

Sungwienwong I, Ferrie JJ, Jun JV, Liu C, Barrett TM, Hostetler ZM, Ieda N, Hendricks A, Muthusamy AK, Kohli RM, Chenoweth DM, Petersson GA, Petersson EJ: Improving the fluorescent probe acridonylalanine through a combination of theory and experiment J Phys Org Chen : DOI: 10.1002/poc.3813,2018.

Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA, Reich TJ, Cogdill AP, Morrissette JJD, DeNizio JE, Reddy S, Hwang Y, Gohil M, Kulikovskaya I, Nazimuddin F, Gupta M, Chen F, Everett JK, Alexander KA, Lin-Shiao E, Gee MH, Liu X, Young RM, Ambrose D, Wang Y, Xu J, Jordan MS, Marcucci KT, Levine BL, Garcia KC, Zhao Y, Kalos M, Porter DL, Kohli RM, Lacey SF, Berger SL, Bushman FD, June CH, Melenhorst JJ: Disruption of TET2 Promotes the Therapeutic Efficacy of CD19-targeted T cells Nature 558 (7709): 307-312,2018.

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Academic Contact Information

502B Johnson Pavilion
Division of Infectious Disease, Department of Medicine
3610 Hamilton Walk
Philadelphia, PA 19104-6073
Phone: 215-573-7523