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The Role of H3.3 histone variant in the pathogenesis of oral Kaposi's Sarcoma

H3.3组蛋白变异在口腔卡波西肉瘤发病机制中的作用

基本信息

批准号：
10418661
负责人：
ROLF F RENNE
金额：
$ 35.53万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-04 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418661
关键词：
AIDS related cancer ATRX gene Acquired Immunodeficiency Syndrome Address Affect B-Lymphocytes Binding Biology Biopsy CRISPR/Cas technology Cell Line Cells Chromatin Chromatin Structure Clinical Collaborations Data Dentistry Deposition Endothelial Cells Epigenetic Process Episome Epithelial Epithelial Cells Equilibrium Etiology Formalin Freezing Gene Expression Genes Genetic Transcription Genome Gingiva Goals Growth HIV Head and neck structure Herpesviridae Histone H3 Histones Horizontal Disease Transmission Hour Human Human Herpesvirus 8 Incidence Individual Infection Kaposi Sarcoma Knock-in Knock-out Lymphoid Lymphoid Cell Lymphoma cell Lymphoproliferative Disorders Lytic Lytic Phase Maintenance Malignant Neoplasms Maps Modification Molecular Chaperones Multicentric Angiofollicular Lymphoid Hyperplasia Mutation Names Nucleosomes Oral Oral cavity Palate Kaposi&apos s Sarcoma Pathogenesis Pathology Pathway interactions Patients Pattern Phenotype Play Post-Translational Protein Processing Primary Infection Process Recombinants Recurrence Regulation Role Saliva Sampling Site Small Interfering RNA Specimen Testing Therapeutic Transformed Cell Line Translating Variant Viral Viral Gene Expression Regulation Viral Genes Viral Genome Viral Proteins Virus Work antiretroviral therapy base cell type centromere protein A chromatin remodeling college comparative epigenome gene product in vivo knock-down latency-associated nuclear antigen latent infection loss of function lytic gene expression lytic replication malignant mouth neoplasm neoplastic cell new therapeutic target novel oral cavity epithelium primary effusion lymphoma transmission process tumor viral transmission

项目摘要

Abstract Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), and two lymphoproliferative diseases: primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KS is the most common oral cancer in human immunodeficiency virus (HIV)-infected patients. The oral cavity is the major site for virus transmission via saliva. Although the incidence of AIDS-KS cases has been reduced in the US due to combination antiretroviral therapy (cART), recent studies suggest recurrence of oral KS in long-term treated AIDS patients. While KS tumor cells are mostly latently infected, and express a limited number of viral genes, gingival epithelial cells in the oral cavity actively replicate KSHV which is important for a) seeding the latency reservoir in B cells after primary infection and b) shedding in the oral cavity and transmission via saliva. Epigenetics and chromatin structure play a central role in the regulation of both transcription and replication. Deregulation, aberrant deposition, and mutations of histone variants such as H3.3, CENP-A, and H2A.Z and their associated chaperones have been implicated in multiple human cancers including head and neck. After de novo infection, KSHV genomes rapidly associate with nucleosomes which acquire specific epigenetic modifications that partition the viral episome into transcriptionally active and silenced domains. While multiple KSHV epigenetic marks have been mapped in lymphoid, epithelial and endothelial cells, the processes and potential host- viral interactions leading to the formation of latency permissive episomes are still poorly understood. Given that the KSHV latency-associated nuclear antigen (LANA) interacts with both chromatin remodelers and H3.3 histone chaperones Daxx, HIRA, and DEK, we hypothesize that H3.3 deposition plays an important role in the establishment and maintenance of KSHV latency. Our preliminary data demonstrate that H3.3 deposition on KSHV episomes can be detected early after de novo infection on episomes of long-term infected cells. Moreover, we demonstrated that genetically disrupting the H3.3 chaperone pathways HIRA and Daxx by CRISPR/Cas9 leads to marked changes in KSHV latency control, associated with alterations in the epigenetic status. We further hypothesize that latency-associated gene products including LANA modulate and or de-regulate histone chaperone pathways during de novo infection and latency. To directly address this hypothesis we propose to mechanistically study histone H3.3 deposition and the formation of histone post translational modifications (PTMs), with the goal of understanding their relationship with respect to viral gene expression and latent/lytic replication. A main aspect of these studies is to investigate how viral gene products interact with and modulate histone variant chaperone pathways. In addition, we use human oral primary epithelial cells which are more lytic than transformed epithelial cell lines to characterize epigenetic changes responsible for their lytic phenotype. Importantly, through a collaboration with Dr. Donald Cohen, College of Dentistry, we propose to establish in vivo epigenomes of oral KS in both formalin-fixed and snap frozen tumor samples. The overall goal is to investigate how histone variant deposition determines latent and lytic infection in a cell type-specific manner. The results may point to KSHV-specific novel therapeutic targets for oral KS.

摘要

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Coordination of transcription, processing, and export of highly expressed RNAs by distinct biomolecular condensates.

DOI：
10.1042/etls20190160
发表时间：
2020-12-11
期刊：
Emerging topics in life sciences
影响因子：
3.8
作者：
Ishov AM;Gurumurthy A;Bungert J
通讯作者：
Bungert J

Inhibition of Mps1 kinase enhances taxanes efficacy in castration resistant prostate cancer.

MPS1激酶的抑制作用增强了抗castratiation抗性前列腺癌中紫杉烷的功效。

DOI：
10.1038/s41419-022-05312-8
发表时间：
2022-10-13
期刊：
CELL DEATH & DISEASE
影响因子：
9
作者：
Sarwar, Sadia;Morozov, Viacheslav M.;Purayil, Hamsa;Daaka, Yehia;Ishov, Alexander M.
通讯作者：
Ishov, Alexander M.

Sex-biased expression is associated with chromatin state in D. melanogaster and D. simulans.

性别偏向表达与黑腹果蝇和拟果蝇中的染色质状态相关。

DOI：
10.1101/2023.01.13.523946
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Nanni,AdalenaV;Martinez,Natalie;Graze,Rita;Morse,Alison;Newman,JeremyRB;Jain,Vaibhav;Vlaho,Srna;Signor,Sarah;Nuzhdin,SergeyV;Renne,Rolf;McIntyre,LaurenM
通讯作者：
McIntyre,LaurenM

Super-enhancer mediated regulation of adult β-globin gene expression: the role of eRNA and Integrator.

DOI：
10.1093/nar/gkab002
发表时间：
2021-02-22
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Gurumurthy A;Yu DT;Stees JR;Chamales P;Gavrilova E;Wassel P;Li L;Stribling D;Chen J;Brackett M;Ishov AM;Xie M;Bungert J
通讯作者：
Bungert J