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.

通过调节元件的突变或负责任的突变对基因组相互作用的放松管制细胞核酶会导致多种疾病。虽然适当基因组基因组的意义从疾病表型中可以看出相互作用，这是基因组循环的基本分子机制调节和转录的直接结果仍然没有很好地连接。这部分源于高度细胞启动子调节的复杂性质，因为它由多个转录因子和增强子控制细胞种群中具有明显噪音的元素。重组Kaposi与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）插发体确定宿主细胞CHAHP（CHD4，ADNP，HP1）蛋白质复合物形成A 稳定的蛋白质复合物与KSHV潜伏期相关的核抗原（LANA），并在维持潜在病毒染色质的诱导性。众所周知，CHAHP综合体限制了细胞增强子的可及性和调节细胞谱系，尽管蛋白质复合物如何调节增强子促销的相互作用仍然未知。在这里，我们假设KSHV延迟延迟开关是由增强剂促销相互作用的产物 Lana-Chahp综合体。在此应用程序中，我们将研究如何将KSHV插曲保持为可诱导的沿着诉状，如果我们可以瞄准蛋白质复合物进行治疗干预。分子作用 LANA/CHAHP蛋白质复合物将从三个不同的角度进行研究。（i）生化，（ii）遗传和（iii）蛋白质复合物结构。通过利用定义的增强器促销对和方便的诱导型迷你病毒染色质，我们将通过剖析CHAHP蛋白复合函数来研究增强子促销法规。这拟议的研究不仅应受益于对KSHV潜伏期开关的理解，还应提供洞察力进入细胞诱导型增强子调节机制。