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

Kevin Y. Kim, Steve B. Huerta, Chie Izumiya, Don Hong Wang, Anthony Martinez, Bogdan Shevchenko, Hsing Jien Kung, Mel Campbell, Yoshihiro Izumiya

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38 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)6782-6793
Number of pages12
JournalJournal of Virology
Issue number12
StatePublished - Jun 2013


ASJC Scopus subject areas

  • Immunology
  • Virology

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