國家衛生研究院 NHRI:Item 3990099045/5375
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    題名: Histone demethylase JMJD2A regulates Kaposi's sarcoma-associated herpesvirus replication and is targeted by a viral transcriptional factor
    作者: Chang, PC;Fitzgerald, LD;Hsia, DA;Izumiya, Y;Wu, CY;Hsieh, WP;Lin, SF;Campbell, M;Lam, KS;Luciw, PA;Tepper, CG;Kung, HJ
    貢獻者: National Institute of Cancer Research
    摘要: The switch between latency and lytic cycle of Kaposi's sarcoma-associated herpesvirus (KSHV) is accompanied by specific alterations of histone codes. Recently, comprehensive analysis of histone modifications of KSHV showed the deposition of H3K27me3 across KSHV genome with two specific regions occupied by the heterochromatin marker H3K9me3. Here, we show that knockdown of JMJD2A, an H3K9me3 demethylase, attenuates viral titers, whereas its overexpression increases KSHV reactivation. JMJD2A is localized in regions of latent viral chromosomes that are deficient in the H3K9me3 mark, indicating that JMJD2A may be responsible for the low level of this mark on viral chromatin. The presence of JMJD2A on the latent genome maintains H3K9 in unmethylated form and signals the "readiness" of specific sets of viral genes to be reactivated. The demethylase activity of JMJD2A is important for KSHV reactivation because a demethylase-deficient mutant cannot restore JMJD2A knockdown phenotype. Interestingly, we found that the KSHV encoded K-bZIP associated with JMJD2A, resulting in the inhibition of demethylase activity of JMJD2A both in vivo and in vitro. Inhibition of JMJD2A by K-bZIP is likely due to a physical interaction which blocks substrate accessibility. A consequence of such an inhibition is increasing global levels of H3K9me3 and gene silencing. Consistently, K-bZIP overexpression resulted in a repression of approximately 80% of the >/=2-fold differentially-regulated genes. The consequences of K-bZIP targeting JMJD2A during viral replication will be discussed. To our knowledge, this is the first description of a viral product shown to be a potent inhibitor of a host cellular histone demethylase.
    日期: 2011-04
    關聯: Journal of Virology. 2011 Apr;85(7):3283-3293.
    Link to: http://dx.doi.org/10.1128/jvi.02485-10
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-538X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000288373000023
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=79952602772
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