Kaposi's sarcoma-Associated herpesvirus (KSHV) latency-Associated nuclear antigen regulates the KSHV epigenome by association with the histone demethylase KDM3A

K.Y. Kim, S.B. Huerta, C. Izumiya, D.-H. Wang, A. Martinez, B. Shevchenko, H.-J. Kung, M. Campbell, Y. Izumiya

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)


Kaposi's sarcoma-associated herpesvirus (KSHV) latent genomes are tethered to host histones to form a minichromosome also known as an "episome." Histones, which are core components of chromatin, are heavily modified by various histone-targetingenzymes. Posttranslational modifications of histones significantly influence accessibility of transcriptional factors and thus have profound effects on gene expression. Recent studies showed that epigenetic marks on the KSHV episome are well organized, exemplified by the absence of histone H3 lysine 9 (H3K9) methylation, a heterochromatic histone mark, from immediate early andlatent gene promoters in naturally infected cells. The present study revealed a mechanistic insight into KSHV epigenome regulationvia a complex consisting of LANA and the H3K9me1/2 histone demethylase JMJD1A/KDM3A. This complex was isolatedfrom HeLa cell nuclear extracts stably expressing LANA and was verified by coimmunoprecipitation analyses and with purifiedproteins. LANA recruitment sites on the KSHV genome inversely correlated with H3K9me2 histone marks in naturally infectedcells, and methylation of H3K9 significantly inhibited LANA binding to the histone H3 tail. Chromatin immunoprecipitationcoupled with KSHV tiling arrays identified the recruitment sites of the complex, while depletion of LANA expression or overexpressionof a KDM3A binding-deficient mutant decreased KDM3A recruitment to the KSHV genome. Finally, ablation ofKDM3A expression from latently KSHV-infected cells significantly inhibited KSHV gene expression, leading to decreased KSHVreplication during reactivation. Taken together, our results suggest that LANA may play a role in regulation of epigenetic markson the KSHV genome, which is in part through association with the histone demethylase KDM3A. © 2013, American Society for Microbiology.
Original languageEnglish
Pages (from-to)6782-6793
Number of pages12
JournalJournal of Virology
Issue number12
Publication statusPublished - Jun 2013
Externally publishedYes


  • histone demethylase
  • histone H3
  • latency associated nuclear antigen
  • protein KDM3A
  • unclassified drug
  • amino terminal sequence
  • article
  • binding site
  • chromatin immunoprecipitation
  • complex formation
  • controlled study
  • embryo
  • epigenetics
  • gene control
  • gene expression regulation
  • genetic association
  • histone methylation
  • human
  • human cell
  • Human herpesvirus 8
  • nonhuman
  • nucleotide sequence
  • priority journal
  • protein binding
  • protein expression
  • protein protein interaction
  • protein purification
  • virus gene
  • virus genome
  • virus latency
  • virus reactivation
  • virus replication
  • Antigens, Viral
  • Chromatin Immunoprecipitation
  • DNA Replication
  • Epigenesis, Genetic
  • Gene Expression Regulation, Viral
  • Genome, Viral
  • HEK293 Cells
  • HeLa Cells
  • Herpesvirus 8, Human
  • Histones
  • Host-Pathogen Interactions
  • Humans
  • Jumonji Domain-Containing Histone Demethylases
  • Nuclear Proteins
  • Oligonucleotide Array Sequence Analysis
  • Virus Latency


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