Wei, Shan
(2022)
GRWD1 mediates Kaposi’s sarcoma-associated herpesvirus epigenetic reprogramming in cellular transformation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) infection is causally associated with numerous cancers. The mechanism of KSHV-induced oncogenesis remains unclear. By performing a CRISPR-Cas9 screening in a model of KSHV-induced cellular transformation of primary cells, we identified epigenetic regulators that were essential for KSHV-induced cellular transformation. Examination of TCGA data sets of the top 9 genes, including glutamate-rich WD repeat containing 1 (GRWD1), a WD40 family protein upregulated by KSHV, that had positive effects on cell proliferation and survival of KSHV-transformed cells (KMM) but not the matched primary cells (MM), uncovered the predictive values of their expressions for patient survival in numerous types of cancer. We revealed global epigenetic remodeling including H3K4me3 epigenetic active mark in KMM cells compared to MM cells. Knockdown of GRWD1 inhibited cell proliferation, cellular transformation, and tumor formation and caused downregulation of the global H3K4me3 mark in KMM cells. GRWD1 interacted with WD repeat domain 5 (WDR5), the core protein of the H3K4 methyltransferase complex, and several H3K4me3 methyltransferases, including myeloid leukemia 2 (MLL2). Knockdown of WDR5 and MLL2 phenocopied GRWD1 knockdown, caused the global reduction of the H3K4me3 mark and altered the expression of similar sets of genes. Transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses further identified common and distinct cellular genes and pathways that were regulated by GRWD1, WDR5, and MLL2. These results indicate that KSHV hijacks the GRWD1-WDR5-MLL2 epigenetic complex to regulate H3K4me3 methylation of specific genes, which is essential for KSHV-induced cellular transformation. Our work has identified an epigenetic complex as a novel therapeutic target for KSHV-induced cancers.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
25 May 2022 |
| Date Type: |
Publication |
| Defense Date: |
28 March 2022 |
| Approval Date: |
25 May 2022 |
| Submission Date: |
20 April 2022 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
139 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
GRWD1; H3 lysine 4 trimethylation; H3K4me3; KS; KSHV; Kaposi’s sarcoma; Kaposi’s sarcoma-associated herpesvirus; MLL2; WD repeat domain 5; WDR5; epigenetic regulators; glutamate-rich WD repeat containing 1; myeloid/lymphoid or mixed-lineage leukemia 2; KMT2B. |
| Related URLs: |
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| Date Deposited: |
26 May 2022 02:26 |
| Last Modified: |
19 May 2023 14:06 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42668 |
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