Junwei Shi, Ph.D.

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Associate 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
B.S. (Biotechnology)
Sun Yat-sen University (China), 2008.
Ph.D. (Molecular and Cellular Biology)
Stony Brook University, SUNY, 2016.
Permanent link
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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:
Roopsha Bandopadhyay, PhD Student
Zhendong Cao, PhD Student
Qingzhou Chen, Postdoctoral Researcher
Chad Komar, MD/PhD Student
Yuqiao Liu, Research Specialist
Bianca Pingul, PhD Student
Diqiu Ren, Postdoctoral Researcher
Deb Sneddon, Program Coordinator
Ping Wang, Postdoc

Selected Publications

Qin K, Lan X, Huang P, Saari MS, Khandros E, Keller CA, Giardine BM, Abdulmalik O, Shi J, Hardison RC, Blobel GA: Molecular basis of polycomb group protein-mediated fetal hemoglobin repression. Blood March 2023.

Sun X, Klingbeil O, Lu B, Wu C, Ballon C, Ouyang M, Wu XS, Jin Y, Hwangbo Y, Huang Y-H, Somerville TD, Chang K, Park J, Chung T, Lyons SK, Shi J, Vogel H, Schulder M, Vakoc CR, Mills AA: BRD8 maintains glioblastoma by epigenetic reprogramming of the p network. Nature 613(7942): 195-202, January 2023.

Qiu J, Xu B, Ye D, Ren D, Wang S, Benci JL, Xu Y, Ishwaran H, Beltra J-C, Wherry EJ, Shi J, Minn AJ: Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction. Nature Cancer 4(1): 43-61, January 2023.

BerrĂ­os KN, Barka A, Gill J, Evitt NH, Gajula KS, Shi J#, Kohli RM# (#co-corresponding author): Cooperativity between Cas9 and AID establishes broad and diversifying mutational footprints in base editors. BioRxiv Preprint, Dec 2022.

Liu Y, Li Q, Alikarami F, Barrett DR, Mahdavi L, Li H, Tang S, Khan TA, Michino M, Hill C, Song L, Yang L, Li Y, Pokharel SP, Stamford AW, Liverton N, Renzetti LM, Taylor S, Watt GF, Ladduwahetty T, Kargman S, Meinke PT, Foley MA, Shi J, Li H, Carroll M, Chen C-W, Gardini A, Maillard I, Huggins DJ, Bernt KM, Wan L: Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia. Cancer Discovery 12(11): 2684-2709, November 2022.

Huang P, Peslak SA, Ren R, Khandros E, Qin K, Keller CA, Giardine B, Bell HW, Lan X, Sharma M, Horton JR, Abdulmalik O, Chou ST, Shi J, Crossley M, Hardison RC, Cheng X, Blobel GA: HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription. Nature Genetics 54(9): 1417-1426, September 2022.

Pingul BY, Huang H, Chen Q, Alikarami F, Zhang Z, Qi J, Bernt KM, Berger SL, Cao Z#, Shi J# (#co-corresponding author): Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia. iScience 25(10): 105139, September 2022.

Qin K, Huang P, Feng R, Keller CA, Peslak SA, Khandros E, Saari M, Lan X, Mayuranathan T, Doerfler PA, Abdulmalik O, Giardine B, Chou ST, Shi J, Hardison RC, Weiss MJ, Blobel GA: Dual function NFI factors control fetal hemoglobin silencing in adult erythroid cells. Nature Genetics May 2022.

Wakabayashi A, Kihiu M, Sharma M, Thrasher AJ, Saari MS, Quesnel-Vallieres M, Abdulmalik O, Peslak SA, Khandros E, Keller CA, Giardine BM, Barash Y, Hardison RC, Shi J, Blobel GA: Identification and characterization of RBM12 as a novel regulator of fetal hemoglobin expression. Blood Advances May 2022.

Cucolo L, Chen Q, Qiu J, Klapholz M, Budinich K, Zhang Z, Shao Y, Brodsky IE, Jordan MS, Gilliland DG, Zhang NR, Shi J, Minn AJ: The interferon-stimulated gene RIPK1 regulates cancer cell intrinsic and extrinsic resistance to immune checkpoint blockade. Immunity 55(4): 671-685, April 2022.

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Last updated: 04/05/2023
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