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Principal Investigator: Yoshihiro Izumiya
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2022
Award: $505,165
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Affinity Chromatography><Alanine><Alkylation><Amino Acid Sequence><BAC clone><BACs><BSL-2 facility><BSL2 facility><Bacterial Artificial Chromosomes><Baculoviridae><Baculoviruses><Basal Transcription Factor><Basal transcription factor genes><Binding><Biochemical><Biochemical Genetics><Biologic Phenomena><Biological Phenomena><Body Tissues><Burkitt Herpesvirus><Burkitt Lymphoma Virus><CHD4><CHD4 gene><Cancers><Cell Body><Cell Communication and Signaling><Cell Line><Cell Lineage><Cell Signaling><CellLine><Cells><Chromatin><Chromatin Structure><Chromodomain Helicase DNA-Binding Protein 4><Clinical><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><DNA><DNA Replication><DNA Synthesis><DNA biosynthesis><DNA-Dependent RNA Polymerase II><Deoxyribonucleic Acid><Disease><Disorder><Docking><Double-Stranded DNA><Drugs><E-B Virus><EB virus><EBV><Electron Cryomicroscopy><Electron Microscopy><Engineering><Enhancer Elements><Enhancers><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Episome><Epstein Barr Virus><Event><Flanking Repeat Sequences><Frequencies><Functional RNA><Gene Activation><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Enhancer Element><Genetic Transcription><Genetic defect><Genetic study><Genome><Genomic Segment><Genomics><Germinoblastic Sarcoma><Germinoblastoma><HHV-4><HHV-8><HHV4><HHV8><Herpesviridae><Herpesviruses><Hi-C><Human Herpesvirus 4><Human Herpesvirus 8><Infection><Infectious Mononucleosis Virus><Intracellular Communication and Signaling><KSHV><Kaposi Sarcoma-Associated Herpes Virus><Kaposi Sarcoma-Associated Herpesvirus><Kaposi sarcoma associated virus><Kaposi sarcoma herpes virus><Kaposi's sarcoma (KS)-associated herpesvirus><Laboratories><Life Cycle><Life Cycle Stages><Link><Lymphoma><Lytic><Maintenance><Malignant Lymphoma><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Maps><Mediating><Medication><Memory><Mercaptans><Mercapto Compounds><Metabolic><Mi2-Beta><Modeling><Molecular><Molecular Interaction><Mutation><Nature><Noise><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nuclear><ORF73 gene product><Oncogenesis><Organism><Outcome><Peptide-based drug><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Play><Population><Primary Protein Structure><Proteins><Proteomics><RNA><RNA Expression><RNA Gene Products><RNA Polymerase B><RNA Polymerase II><RNA Seq><RNA sequencing><RNAseq><Recombinant DNA><Recombinant DNA Molecular Biology><Recombinants><Regulation><Regulatory Element><Resolution><Reticulolymphosarcoma><Ribonucleic Acid><Risk Factors><Role><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small RNA><Stimulus><Strains Cell Lines><Structure><Sulfhydryl Compounds><Surface><Terminal Repeat><Terminal Repeat Sequences><Therapeutic Intervention><Thiols><Tissues><Trans-Acting Factors><Trans-Activators><Transactivators><Transcription><Transcription Factor Proto-Oncogene><Transcription Initiation Site><Transcription Start Site><Transcription factor genes><Untranslated RNA><Viral><Viral Latency><Virus Latency><Virus-HHV8><affinity purification><base><biological signal transduction><biosafety level 2 facility><cell killing><cellular targeting><cost effective><cryo-EM><cryoEM><cryogenics><cultured cell line><disease phenotype><drug/agent><ds-DNA><dsDNA><enhancer sequence><genetic enhancer sequence><genome mutation><genomic region><herpes virus><infected B cell><infected B lymphocyte><insight><institutional biosafety committee><intervention therapy><kaposi's sarcoma herpesvirus><kaposi's sarcoma-associated human herpesvirus><latency-associated nuclear antigen><latent infection><life course><living system><lytic gene expression><lytic replication><lytic viral replication><lytic virus replication><malignancy><mutant><neoplasm/cancer><noncoding><nuclease><peptide drug><promoter><promotor><protein complex><protein sequence><social role><stem><sulfhydryl group><therapeutic peptide><tissue culture><tool><transcription factor><transcriptome sequencing><transcriptomics><tumor><tumorigenesis><yeast genetics>