Junwei Shi, Ph.D.

faculty photo
Assistant Professor of Cancer Biology
Assistant Investigator, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania
Core member, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania
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:
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

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 September 2022 online.

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 2022 in press.

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.

Giles JR, Manne S, Freilich E, Oldridge DA, Baxter AE, George S, Chen Z, Huang H, Chilukuri L, Carberry M, Giles L, Weng N-P P, Young RM, June CH, Schuchter LM, Amaravadi RK, Xu X, Karakousis GC, Mitchell TC, Huang AC, Shi J, Wherry EJ: Human epigenetic and transcriptional T cell differentiation atlas for identifying functional T cell-specific enhancers. Immunity 55(3): 557-574, March 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 In Press 2022.

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, and 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.

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Last updated: 09/14/2022
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