Jen-Tsan Chi

Positions:

Associate Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Assistant Professor of Medicine

Medicine, Rheumatology and Immunology
School of Medicine

Assistant Professor in Radiation Oncology

Radiation Oncology
School of Medicine

Associate Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1991

National Taiwan University

Ph.D. 2000

Stanford University

Postdoctoral Research, Biochemistry

Stanford University

Grants:

Metabolic regulation of KLHL proteins through O-glycosylation

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Storage-specific erythrocyte gene signatures to detect autologous transfusion

Administered By
Molecular Genetics and Microbiology
Role
Principal Investigator
Start Date
End Date

Detect autologous transfusion by novel separation and characterization of RBC storage exosomes

Administered By
Molecular Genetics and Microbiology
Role
Principal Investigator
Start Date
End Date

Small RNA transcriptome as novel approaches to detect autologous blood transfusion

Administered By
Molecular Genetics and Microbiology
Role
Principal Investigator
Start Date
End Date

Comparison of oxidant damage, Nrf2 characteristics, and gene modification of cord blood versus plerixafor-mobilized adult CD34+ cells from sickle cell disease patients

Administered By
Molecular Genetics and Microbiology
Role
Principal Investigator
Start Date
End Date

Publications:

Latent transcriptional variations of individual Plasmodium falciparum uncovered by single-cell RNA-seq and fluorescence imaging.

Malaria parasites follow a complex life cycle that consists of multiple stages that span from the human host to the mosquito vector. Among the species causing malaria, Plasmodium falciparum is the most lethal, with clinical symptoms manifesting during the intraerythrocytic developmental cycle (IDC). During the IDC, P. falciparum progresses through a synchronous and continuous cascade of transcriptional programming previously established using population analyses. While individual parasites are known to exhibit transcriptional variations to evade the host immune system or commit to a sexual fate, such rare expression heterogeneity is largely undetectable on a population level. Therefore, we combined single-cell RNA-sequencing (scRNA-seq) on a microfluidic platform and fluorescence imaging to delineate the transcriptional variations among individual parasites during late asexual and sexual stages. The comparison between asexual and sexual parasites uncovered a set of previously undefined sex-specific genes. Asexual parasites were segregated into three distinct clusters based on the differential expression of genes encoding SERAs, rhoptry proteins, and EXP2 plus transporters. Multiple pseudotime analyses revealed that these stage-specific transitions are distinct. RNA fluorescent in situ hybridization of cluster-specific genes validated distinct stage-specific expression and transitions during the IDC and defined the highly variable transcriptional pattern of EXP2. Additionally, these analyses indicated huge variations in the stage-specific transcript levels among parasites. Overall, scRNA-seq and RNA-FISH of P. falciparum revealed distinct stage transitions and unexpected degrees of heterogeneity with potential impact on transcriptional regulation during the IDC and adaptive responses to the host.
Authors
Walzer, KA; Fradin, H; Emerson, LY; Corcoran, DL; Chi, J-T
MLA Citation
Walzer, Katelyn A., et al. “Latent transcriptional variations of individual Plasmodium falciparum uncovered by single-cell RNA-seq and fluorescence imaging..” Plos Genet, vol. 15, no. 12, Dec. 2019. Pubmed, doi:10.1371/journal.pgen.1008506.
URI
https://scholars.duke.edu/individual/pub1425508
PMID
31856180
Source
pubmed
Published In
Plos Genet
Volume
15
Published Date
Start Page
e1008506
DOI
10.1371/journal.pgen.1008506

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

Abstract The molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between primary and recurrent breast tumor cells from a murine model of breast cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is dramatically re-expressed in recurrent breast tumor cells by an epigenetic mechanism. Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on extracellular cystine and undergo programmed necrosis upon cystine deprivation. The induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that paradoxically confers on tumors both growth advantage and necrotic vulnerability, providing potential strategies to eradicate recurrent tumors.
Authors
Lin, C-C; Mabe, N; Lin, Y-T; Yang, W-H; Tang, X; Hong, L; Sun, T; Yao, T-P; Alvarez, J; Chi, J-T
MLA Citation
URI
https://scholars.duke.edu/individual/pub1425509
Source
epmc
Published Date
DOI
10.1101/679332

Glycosylation of gigaxonin regulates intermediate filaments: Novel molecular insights into giant axonal neuropathy: supplemental information

Gigaxonin (also known as KLHL16) is an E3 ligase adaptor protein that promotes the ubiquitination and degradation of intermediate filament (IF) proteins. Mutations in human gigaxonin cause the fatal neurodegenerative disease giant axonal neuropathy (GAN), in which IF proteins accumulate and aggregate in axons throughout the nervous system, impairing neuronal function and viability. Despite this pathophysiological significance, the upstream regulation and downstream effects of normal and aberrant gigaxonin function remain incompletely understood. Here, we report that gigaxonin is modified by O-linked-beta-N-acetylglucosamine (O-GlcNAc), a prevalent form of intracellular glycosylation, in a nutrient- and growth factor-dependent manner. Mass spectrometry analyses of human gigaxonin revealed nine candidate sites of O-GlcNAcylation, two of which - serine 272 and threonine 277 - are required for its ability to mediate IF turnover in novel gigaxonin-deficient human cell models that we created. Taken together, these results suggest that nutrient-responsive gigaxonin O-GlcNAcylation forms a regulatory link between metabolism and IF proteostasis. Our work may have significant implications for understanding the non-genetic modifiers of GAN phenotypes and for the optimization of gene therapy for this disease.
Authors
CHEN, PO-HAN; Smith, T; Hu, J; Pan, S; Smith, A; Lu, A; Chi, J-T; Boyce, M
URI
https://scholars.duke.edu/individual/pub1425510
Source
epmc
Published Date
DOI
10.1101/530303

A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer.

Ovarian cancer is the deadliest gynecologic cancer. Despite recent advances, clinical outcomes remain poor, necessitating novel therapeutic approaches. To investigate metabolic susceptibility, we performed nutrigenetic screens on a panel of clear cell and serous ovarian cancer cells and identified cystine addiction and vulnerability to ferroptosis, a novel form of regulated cell death. Our results may have therapeutic potential, but little is known about the determinants of ferroptosis susceptibility in ovarian cancer. We found that vulnerability to ferroptosis in ovarian cancer cells is enhanced by lower cell confluency. Because the Hippo pathway effectors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are recognized as sensors of cell density, and TAZ is the predominant effector in the tested ovarian cancer cell lines, we investigated the role of TAZ in ferroptosis of ovarian cancer. TAZ removal confers ferroptosis resistance, while TAZS89A overexpression sensitizes cells to ferroptosis. In addition, we found that lower TAZ level in chemo-resistant recurrent ovarian cancer is responsible for reduced ferroptosis susceptibility. The integrative genomic analysis identified ANGPTL4 as a direct TAZ-regulated target gene that sensitizes ferroptosis by activating NOX2. Collectively, cell density-regulated ferroptosis in ovarian cancer is mediated by TAZ through the regulation of the ANGPTL4-NOX2 axis, suggesting therapeutic potentials for ovarian cancers and other TAZ-activated tumors. IMPLICATIONS: This study reveals that TAZ promotes ferroptosis in ovarian cancers by regulating ANGPTL4 and NOX, offering a novel therapeutic potential for ovarian tumors with TAZ activation.
Authors
MLA Citation
Yang, Wen-Hsuan, et al. “A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer..” Mol Cancer Res, Oct. 2019. Pubmed, doi:10.1158/1541-7786.MCR-19-0691.
URI
https://scholars.duke.edu/individual/pub1416673
PMID
31641008
Source
pubmed
Published In
Mol Cancer Res
Published Date
DOI
10.1158/1541-7786.MCR-19-0691

The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma.

Despite recent advances, the poor outcomes in renal cell carcinoma (RCC) suggest novel therapeutics are needed. Ferroptosis is a form of regulated cell death, which may have therapeutic potential toward RCC; however, much remains unknown about the determinants of ferroptosis susceptibility. We found that ferroptosis susceptibility is highly influenced by cell density and confluency. Because cell density regulates the Hippo-YAP/TAZ pathway, we investigated the roles of the Hippo pathway effectors in ferroptosis. TAZ is abundantly expressed in RCC and undergoes density-dependent nuclear or cytosolic translocation. TAZ removal confers ferroptosis resistance, whereas overexpression of TAZS89A sensitizes cells to ferroptosis. Furthermore, TAZ regulates the expression of Epithelial Membrane Protein 1 (EMP1), which, in turn, induces the expression of nicotinamide adenine dinucleotide phosphate (NADPH) Oxidase 4 (NOX4), a renal-enriched reactive oxygen species (ROS)-generating enzyme essential for ferroptosis. These findings reveal that cell density-regulated ferroptosis is mediated by TAZ through the regulation of EMP1-NOX4, suggesting its therapeutic potential for RCC and other TAZ-activated tumors.
Authors
Yang, W-H; Ding, C-KC; Sun, T; Rupprecht, G; Lin, C-C; Hsu, D; Chi, J-T
MLA Citation
Yang, Wen-Hsuan, et al. “The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma..” Cell Rep, vol. 28, no. 10, Sept. 2019, pp. 2501-2508.e4. Pubmed, doi:10.1016/j.celrep.2019.07.107.
URI
https://scholars.duke.edu/individual/pub1368730
PMID
31484063
Source
pubmed
Published In
Cell Reports
Volume
28
Published Date
Start Page
2501
End Page
2508.e4
DOI
10.1016/j.celrep.2019.07.107