Junwei Shi, Ph.D.

faculty photo
Assistant Professor of Cancer Biology
Department: Cancer Biology

Contact information
421 Curie Blvd., 610 BRB II/III
Philadelphia, PA 19104-6160
Office: 215-746-5733
Fax: 215-573-6725
Lab: 215-746-3614
Education:
B.S. (Biotechnology)
Sun Yat-sen University (China), 2008.
Ph.D. (Molecular and Cellular Biology)
Stony Brook University, SUNY, 2016.
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Description of Research Expertise

Current Research
The physiological effects of cancer are a manifestation of the genetic abnormalities that cause the disease. While much progress has been made in the understanding of such genetic perturbations, scientists still struggle to effectively identify, understand, and treat cancer-causing mutations. This is due to the fast-paced evolution of the disease, and the accumulation of novel mutations that permit cell survival even in the harsh environment created by a therapeutic. CRISPR is a gene-editing technology that couples the elegance of base complementarity with the enzymatic activity of a DNA nuclease in order to introduce mutations into target loci. CRISPR technologies help advance our understanding of the genetic perturbations that contribute to cancer maintenance.

Current areas of interest within the lab include: (1) Defining the functional importance of epigenetic regulators in leukemia, (2) Development and optimization of AsCas12a for multiplex genetic dropout screening, and (3) Developing new functional genomic tools.

Research Details
While whole exome sequencing of the leukemia cancer genome revealed many oncogene mutations, few of these genetic alterations lead to directly actionable therapeutic opportunities. A major objective of the lab is to annotate and dissect these genetic vulnerabilities in leukemia. To approach this, we use our highly developed domain-focused CRISPR genetic knockout screening technology, where CRISPR-mediated mutagenesis is directed to gene sequences encoding critical protein domains. This method generates a larger fraction of functional null-alleles, which increase the severity in a negative selection-based genetic screen. In contrast to RNA interference-based methods or prior CRISPR-based screening approaches, this new method is not only more efficient than other screening approaches, but also has the potential to evaluate protein domain function directly from genetic screening, and may allow high-throughput identification of protein domains that are suitable drug targets in cancer. Coupling functional genomics screening, biochemical assays, and pre-clinical mouse models, we investigate the aberrant transcription signaling networks of leukemia and explore them as potential therapeutic opportunities. Since genetic screenings are only as successful as the underlying technology, a major focus of the lab is to further optimize and expand our screening toolbox. Projects are underway to engineer different Cas proteins for multiplex genetic screening using a variety of methods, including structure-guided rational design and directed evolution. Our ultimate goal is to uncover complex genetic interactions in leukemia that are therapeutically tractable.

Lab Members:

Diqiu Ren, Postdoctoral Researcher
Qingzhou Chen, Postdoctoral Researcher
Zhendong Cao, Graduate Student
Niklaus Evitt, Graduate Student
Chad Komar, Graduate Student
Kurtis McCannell, Graduate Student
Bianca Pingul, Graduate Student
Lizzie Freilich, Research Specialist
Deb Sneddon, Program Coordinator

Selected Publications

BerrĂ­os KN, Evitt NH, DeWeerd RA, Ren D, Luo M, Barka A, Wang T, Bartman CR, Lan Y, Green AM, Shi J#, and Kohli RM# (#co-corresponding author): Controllable genome editing with split-engineered base editors. Nature Chemical Biology October 2021.

Cao Z, Budinich KA, Huang H, Ren D, Lu B, Zhang Z, Chen Q, Zhou Y, Huang Y-H, Alikarami F, Kingsley M, Lenard AK, Wakabayashi A, Khandros E, Bailis W, Qi J, Carroll MP, Blobel GA, Faryabi RB, Bernt KM, Berger SL, Shi J: ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency. Molecular Cell 81(17): 3604-3622, September 2021.

Chen Z, Arai E, Khan O, Zhang Z, Ngiow SF, He Y, Huang H, Manne S, Cao Z, Baxter AE, Cai Z, Freilich E, Ali MA, Giles JR, Wu JE, Greenplate AR, Hakeem MA, Chen Q, Kurachi M, Nzingha K, Ekshyyan V, Mathew D, Wen Z, Speck NA, Battle A, Berger SL, Wherry EJ#, and Shi J# (#co-corresponding author): In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer. Cell 184(5): 1262-1280, March 2021.

Yao C, Lou, G Sun H-W, Zhu Z, Sun Y, Chen Z, Chauss D, Moseman EA, Cheng J, D'Antonio MA, Shi W, Shi J, Kometani K, Kurosaki, T Wherry EJ, Afzali B, Gattinoni L, Zhu Y, McGavern DB, O'Shea JJ, Schwartzberg PL and Wu T: BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8 + T cells. Nature Immunology 22(3): 370-380, March 2021.

Verma P, Zhou Y, Cao Z, Deraska PV, Deb M, Arai E, Li W, Shao Y, Puentes L, Li Y, Patankar S, Mach RH, Faryabi RB, Shi J# and Greenberg RA# (#co-corresponding author): ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination deficient cells. Nature Cell Biology 23(2): 160-171, February 2021.

Torre EA, Arai E, Bayatpour S, Beck LE, Emert BL, Shaffer SM, Mellis IA, Budinich KA, Weeraratna A, Shi J#, Raj A# (#co-corresponding author): Genetic screening for single-cell variability modulators driving therapy resistance. Nature Genetics 53(1): 76-85, January 2021 Notes:

Lan X, Ren R, Feng R, Ly LC, Lan Y, Zhang Z, Aboreden N, Qin K, Horton JR, Grevet JD, Mayuranathan T, Abdulmalik O, Keller CA, Giardine B, Hardison RC, Crossley M, Weiss MJ, Cheng X, Shi J# and Blobel GA# (#co-corresponding author): ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression. Molecular Cell 81(2): 239-254, January 2021.

Peslak SA, Khandros E, Huang P, Lan X, Geronimo CL, Grevet JD, Abdulmalik O, Zhang Z, Giardine BM, Keller CA, Shi J, Hardison RC and Blobel GA: HRI depletion cooperates with pharmacologic inducers to elevate fetal hemoglobin and reduce sickle cell formation. Blood Advances 4(18): 4560-4572, Sep 2020.

Gier RA, Budinich KA, Evitt NH, Cao Z, Freilich E, Chen Q, Qi J, Lan Y, Kohli R, and Shi J#: High-performance CRISPR-Cas12a genome editing for combinatorial genetic screening. Nature Communications 11(1): 3455, July 2020.

Huang P, Peslak SA, Lan X, Khandros E, Yano JA, Sharma M, Keller CA, Giardine B, Qin K, Abdulmalik O, Hardison RC, Shi J* and Blobel GA* (*co-corresponding author): The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression. Blood 135(24): 2121-2132, June 2020.

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Last updated: 11/23/2021
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