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Studies on Epigenetically Active Latent Chromatin Maintenance

表观遗传活性潜在染色质维持的研究

基本信息

批准号：
10570202
负责人：
Yoshihiro Izumiya
金额：
$ 52.98万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-10 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570202
关键词：
Affinity Chromatography Alanine Alkylation Amino Acid Sequence Authorization documentation Bacterial Artificial Chromosomes Baculoviruses Binding Biochemical Biological Phenomena CHD4 gene Cell Line Cell Lineage Cells Chromatin Chromatin Structure Clinical Complex Cryoelectron Microscopy DNA DNA biosynthesis Disease Docking Engineering Enhancers Enzymes Epigenetic Process Episome Event Frequencies Gene Activation Genes Genetic Genetic Enhancer Element Genetic Transcription Genetic study Genome Genomic Segment Genomics Herpesviridae Hi-C Human Herpesvirus 4 Human Herpesvirus 8 Infection Laboratories Life Cycle Stages Link Lymphoma Lytic Maintenance Malignant Neoplasms Mammalian Cell Maps Mediating Memory Metabolic Modeling Molecular Mutation Nature Noise Nuclear Organism Outcome Peptides Pharmaceutical Preparations Phenotype Play Population Proteins Proteomics RNA RNA Polymerase II Recombinant DNA Recombinants Regulation Regulatory Element Resolution Risk Factors Role Signal Transduction Site Small RNA Stimulus Structure Sulfhydryl Compounds Surface Terminal Repeat Sequences Therapeutic Intervention Tissues Trans-Activators Transcription Initiation Site Untranslated RNA Viral Virus Latency authority biosafety level 2 facility cell killing cellular targeting cost effective disease phenotype ds-DNA infected B cell insight institutional biosafety committee latency-associated nuclear antigen latent infection lytic gene expression lytic replication meter mutant nuclease peptide drug promoter protein complex stem tissue culture tool transcription factor transcriptome sequencing transcriptomics tumor tumorigenesis yeast genetics

项目摘要

Deregulation of genome interactions through mutations at regulatory elements or mutation of responsible cellular nuclear enzymes result in multiple disorders. Although the significance of proper genomic-genomic interactions has been seen from disease phenotypes, the underlying molecular mechanisms of genomic looping regulation and the direct outcome of transcription are still not well connected. This partly stems from the highly complex nature of cellular promoter regulation, since it is controlled by multiple transcriptional factors and enhancer elements with significant noise within cell populations. Transcriptomics, genomics, and proteomics studies with recombinant Kaposi's sarcoma-associated herpesvirus (KSHV) episomes identified that the host cellular ChAHP (CHD4, ADNP, HP1) protein complex forms a stable protein complex with KSHV latency associated nuclear antigen (LANA) and plays essential roles in maintaining the inducibility of latent viral chromatin. The ChAHP complex is known to restrict cellular enhancer accessibility and regulates cell lineage, although how the protein complex regulates enhancer-promoter interaction remains unknown. Here, we hypothesize that the KSHV latency-lytic switch is a product of enhancer-promoter interactions regulated by the LANA-ChAHP complex. In this application, we will study how the KSHV episome is maintained as an inducible episome and if we can target the protein complex for therapeutic intervention. The molecular action of the LANA/ChAHP protein complex will be studied from three different perspectives; (i) biochemical, (ii) genetic, and (iii) protein complex structure. By taking advantage of defined enhancer-promoter pairs and convenient inducible mini viral chromatin, we will study enhancer-promoter regulations by dissecting ChAHP protein complex function. The proposed studies should not only benefit the understanding of the KSHV latency-lytic switch, but also provide insight into cellular inducible enhancer regulatory mechanisms.

基因组相互作用的失调通过调控元件的突变或负责基因组相互作用的突变来实现。细胞核酶导致多种疾病。虽然正确的基因组学的意义相互作用已经从疾病表型中看到，基因组循环的潜在分子机制调控和转录的直接结果仍然没有很好地联系起来。部分原因是，细胞启动子调控的复杂性，因为它是由多个转录因子和增强子控制的在细胞群中具有显著噪声的元素。重组卡波西肉瘤相关的转录组学、基因组学和蛋白质组学研究疱疹病毒（KSHV）附加体鉴定出宿主细胞ChAHP（CHD 4，ADNP，HP 1）蛋白复合物形成一个与KSHV潜伏相关核抗原（拉娜）形成稳定的蛋白复合物，在维持KSHV潜伏相关核抗原（LANA）潜伏病毒染色质的诱导。已知ChAHP复合物限制细胞增强子可及性，调节细胞谱系，尽管蛋白质复合物如何调节增强子-启动子相互作用仍然未知。在此，我们假设KSHV潜伏裂解开关是由增强子-启动子相互作用调节的产物， LANA-ChAHP综合体。在本申请中，我们将研究KSHV附加体是如何维持作为诱导型附加体，以及我们是否可以靶向蛋白质复合物进行治疗干预。的分子作用将从三个不同的角度研究拉娜/ChAHP蛋白复合物;（i）生物化学，（ii）遗传，和（iii）蛋白质复合体结构通过利用确定的增强子-启动子对和方便的诱导型微病毒染色质，我们将研究增强子-启动子调控解剖ChAHP蛋白复合物的功能。的拟议的研究不仅有助于理解KSHV潜伏-裂解开关，而且还提供了深入了解转化为细胞诱导增强子调节机制。