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

TY - JOUR

T1 - Kaposi's sarcoma-Associated herpesvirus (KSHV) latency-Associated nuclear antigen regulates the KSHV epigenome by association with the histone demethylase KDM3A

AU - Kim, K.Y.

AU - Huerta, S.B.

AU - Izumiya, C.

AU - Wang, D.-H.

AU - Martinez, A.

AU - Shevchenko, B.

AU - Kung, H.-J.

AU - Campbell, M.

AU - Izumiya, Y.

N1 - 引用次數:30 Export Date: 5 March 2018 CODEN: JOVIA 通訊地址: Izumiya, Y.; Department of Dermatology, University of California, School of Medicine, Davis, United States; 電子郵件: yizumiya@ucdavis.edu 分析序列編號: GENBANK: NC_009333; 化學物質/CAS: Antigens, Viral; Histones; Jumonji Domain-Containing Histone Demethylases, 1.14.11.-; KDM3A protein, human, 1.14.11.-; Nuclear Proteins; latency-associated nuclear antigen 參考文獻: Cesarman, E., Chang, Y., Moore, P.S., Said, J.W., Knowles, D.M., Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas (1995) N. Engl. J. Med., 332, pp. 1186-1191; Dupin, N., Fisher, C., Kellam, P., Ariad, S., Tulliez, M., Franck, N., van Marck, E., Boshoff, C., Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma (1999) Proc. Natl. Acad. Sci. 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PY - 2013/6

Y1 - 2013/6

N2 - 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.

AB - 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.

KW - histone demethylase

KW - histone H3

KW - latency associated nuclear antigen

KW - protein KDM3A

KW - unclassified drug

KW - amino terminal sequence

KW - article

KW - binding site

KW - chromatin immunoprecipitation

KW - complex formation

KW - controlled study

KW - embryo

KW - epigenetics

KW - gene control

KW - gene expression regulation

KW - genetic association

KW - histone methylation

KW - human

KW - human cell

KW - Human herpesvirus 8

KW - nonhuman

KW - nucleotide sequence

KW - priority journal

KW - protein binding

KW - protein expression

KW - protein protein interaction

KW - protein purification

KW - virus gene

KW - virus genome

KW - virus latency

KW - virus reactivation

KW - virus replication

KW - Antigens, Viral

KW - Chromatin Immunoprecipitation

KW - DNA Replication

KW - Epigenesis, Genetic

KW - Gene Expression Regulation, Viral

KW - Genome, Viral

KW - HEK293 Cells

KW - HeLa Cells

KW - Herpesvirus 8, Human

KW - Histones

KW - Host-Pathogen Interactions

KW - Humans

KW - Jumonji Domain-Containing Histone Demethylases

KW - Nuclear Proteins

KW - Oligonucleotide Array Sequence Analysis

KW - Virus Latency

U2 - 10.1128/JVI.00011-13

DO - 10.1128/JVI.00011-13

M3 - Article

VL - 87

SP - 6782

EP - 6793

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 12

ER -