Regulation of the Epstein-Barr Virus Lytic Switch

Epstein-Barr 病毒裂解开关的调节

• 批准号: 10643950
• 负责人: Benjamin Elison Gewurz
• 金额: $ 50.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-06 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643950
• 关键词: 3-Dimensional; Adult; Antigens; Architecture; Auxins; B-Lymphocytes; BZLF1 gene; Binding; Binding Sites; CRISPR screen; Cell Compartmentation; Cell Nucleus; Cells; ChIP-seq; Chromatin Conformation Capture and Sequencing; Chromatin Loop; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cues; DNA Polymerase II; EBV-associated disease; Engineering; Epigenetic Process; Epithelium; Epstein-Barr Virus latency; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genome; Hairy Leukoplakia; Human Genome; Human Herpesvirus 4; Immediate-Early Genes; Immune Evasion; Immune response; Immunoglobulins; Infection; Infectious Mononucleosis; Integration Host Factors; Knowledge; Learning; Location; Lymphoma; Lytic; Lytic Phase; Lytic Virus; Malignant Neoplasms; Malignant neoplasm of nasopharynx; Maps; Mediator; Memory B-Lymphocyte; Methylation; Molecular Conformation; Nasopharynx Carcinoma; Oral cavity; PRDM1 gene; Pathway interactions; Phosphorylation; Physiological; Proto-Oncogene Proteins c-myc; RNA; Regulation; Repression; Resolution; Role; Saliva; Series; Stomach Carcinoma; Structure; System; Therapeutic; Tonsil; Transcription Factor AP-1; Transcriptional Regulation; Viral; Viral Genome; Viral Proteins; Virion; Withdrawal; Xenograft procedure; antagonist; cohesin; crosslink; ds-DNA; genome-wide; in vivo; insight; lytic replication; malignant stomach neoplasm; novel therapeutic intervention; plasma cell differentiation; programs; promoter; release factor; response; single molecule; transcription factor; transmission process; tumorigenesis; viral genomics

Abstract Epstein-Barr virus (EBV) establishes lifelong infection in 95% of adults worldwide. EBV causes infectious mononucleosis, lymphomas, nasopharyngeal and gastric cancer, and oral hairy leukoplakia. EBV is transmitted between hosts through saliva, from which it translocates across the oral cavity and tonsillar epithelium to reach the B-cell compartment. Upon B-cell infection, the ~170 kilobase linear double-stranded DNA (dsDNA) EBV genome is delivered to the nucleus. EBV then uses a series of latency programs to navigate the B-cell compartment, and colonize the memory B-cell compartment. Ultimately, to spread between cells and to the tonsillar epithelium for transfer to a new host, EBV must undergo lytic replication, in which nearly 80 viral proteins are expressed and infectious virion are produced. Lytic replication is increasingly implicated in oncogenesis. Yet, much remains to be learned about how the viral lytic switch is controlled. We therefore used a human genome-wide CRISPR/Cas9 screen to identify host factors that control the viral lytic switch. Our analyses a network of host factors that repress lytic reactivation, centered on the transcription factor MYC, including cohesins, FACT, STAGA, and Mediator. Depletion of MYC or factors important for MYC expression, reactivated the lytic cycle, including in Burkitt xenografts. MYC bound the EBV genome origin of lytic replication and suppressed its looping to the lytic cycle initiator BZLF1 promoter. Our central hypothesis is that the MYC:MAX control the EBV lytic switch through regulation of viral genome loop extrusion. Our Aims are to (1) Define key MYC roles in regulation of oriLyt loop extrusion to control the EBV lytic switch; (2) Define MYC-gated cohesin roles in regulation of oriLyt loop extrusion in EBV lytic switch control (3) Define MYC-gated CTCF roles in regulation of oriLyt loop extrusion to control the EBV lytic switch. Collectively, these studies are expected to identify how EBV subverts host DNA loop extrusion pathways to control the viral lytic switch. Our studies may therefore support strategies to develop rational lytic induction therapeutic therapies for EBV-associated diseases.

摘要

项目成果

Characterization of Target Gene Regulation by the Two Epstein-Barr Virus Oncogene LMP1 Domains Essential for B-cell Transformation.

B 细胞转化所必需的两个 Epstein-Barr 病毒癌基因 LMP1 结构域对靶基因调控的表征。

• DOI: 10.1101/2023.04.10.536234
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Mitra,Bidisha;Beri,NinaRose;Guo,Rui;Burton,EricM;Murray-Nerger,LauraA;Gewurz,BenjaminE
• 通讯作者: Gewurz,BenjaminE