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.

抽象的 Kaposi的肉瘤相关疱疹病毒（KSHV）是Kaposi的肉瘤（KS）的病因学者，和两种淋巴增生性疾病：一级积液淋巴瘤（PEL）和多中心castleman的疾病疾病（MCD）。 KS是人类免疫缺陷病毒（HIV）感染的最常见的口腔癌患者。口腔是通过唾液传播病毒的主要部位。虽然发生率由于联合抗逆转录病毒疗法（CART），美国的AIDS-KS病例已减少研究表明，长期治疗的艾滋病患者的口服KS复发。而KS肿瘤细胞是主要感染了潜在的感染，并表达有限数量的病毒基因，牙龈上皮细胞口腔积极复制KSHV，这对于A）在B细胞中播种潜伏期储存库很重要原发性感染和b）在口腔中脱落并通过唾液传播。表观遗传学和染色质结构在转录和复制的调节中起着核心作用。 H3.3，CENP-A和 H2A.Z及其相关的伴侣与多种人类癌症有关包括头和颈。从头感染后，KSHV基因组迅速与核小体获得特定的表观遗传修饰，将病毒偶发分配到转录活性和沉默的域。而多个KSHV表观遗传标记具有被映射在淋巴样，上皮和内皮细胞中，过程和潜在宿主 - 病毒相互作用导致形成潜伏期允许的发作仍然很差理解。鉴于KSHV潜伏相关的核抗原（LANA）与染色质重塑剂和H3.3组蛋白伴侣DAXX，HIRA和DEK，我们假设H3.3沉积在建立和维护中起着重要作用 KSHV延迟。我们的初步数据表明，H3.3对KSHV促进的沉积可以从从头感染后早期就长期感染细胞的发作。而且，我们证明，通过基因破坏H3.3伴侣途径Hira和Daxx CRISPR/CAS9导致KSHV延迟控制的明显变化，与改变有关表观遗传状态。我们进一步假设与潜伏期相关的基因产物，包括 LANA在从头感染期间调节和 /或脱离调节组蛋白伴侣途径潜伏期。为了直接解决这一假设，我们提出机械学研究组蛋白H3.3 沉积和组蛋白的形成后翻译后修饰（PTMS），目的是了解他们在病毒基因表达和潜在/裂解方面的关系复制。这些研究的一个主要方面是研究病毒基因产物如何与并调节组蛋白变体伴侣途径。此外，我们使用人类口服主要上皮比转化的上皮细胞系更裂解的细胞表征表观遗传负责其裂解表型的变化。重要的是，通过与Dr. 牙科学院唐纳德·科恩（Donald Cohen 福尔马林固定和快照冷冻的肿瘤样品。总体目标是研究组蛋白变体沉积以细胞类型特异性方式决定潜在和裂解感染。结果可能指出针对口服KS的KSHV特异性新型治疗靶标。

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.

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