Histone demethylase JMJD2A regulates Kaposi's sarcoma-associated herpesvirus replication and is targeted by a viral transcriptional factor

Pei Ching Chang, Latricia D. Fitzgerald, Datsun A. Hsia, Yoshihiro Izumiya, Chun Yi Wu, Wen Ping Hsieh, Su Fang Lin, Mel Campbell, Kit Lam, Paul A Luciw, Clifford G Tepper, Hsing-Jien Kung

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Abstract

The switch between the latency and lytic cycles 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 the 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 the 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 ∼80% of the ≥2-fold differentially regulated genes compared to results for the uninduced control cells. 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.

Original languageEnglish (US)
Pages (from-to)3283-3293
Number of pages11
JournalJournal of Virology
Volume85
Issue number7
DOIs
StatePublished - Apr 2011

Fingerprint

Histone Demethylases
Human herpesvirus 8
Human Herpesvirus 8
histones
transcription factors
Histone Code
Genome
genome
Viral Genes
Heterochromatin
Gene Silencing
gene silencing
heterochromatin
virus replication
viral load
Chromatin
chromatin
genes
Chromosomes
chromosomes

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Histone demethylase JMJD2A regulates Kaposi's sarcoma-associated herpesvirus replication and is targeted by a viral transcriptional factor. / Chang, Pei Ching; Fitzgerald, Latricia D.; Hsia, Datsun A.; Izumiya, Yoshihiro; Wu, Chun Yi; Hsieh, Wen Ping; Lin, Su Fang; Campbell, Mel; Lam, Kit; Luciw, Paul A; Tepper, Clifford G; Kung, Hsing-Jien.

In: Journal of Virology, Vol. 85, No. 7, 04.2011, p. 3283-3293.

Research output: Contribution to journalArticle

Chang, Pei Ching ; Fitzgerald, Latricia D. ; Hsia, Datsun A. ; Izumiya, Yoshihiro ; Wu, Chun Yi ; Hsieh, Wen Ping ; Lin, Su Fang ; Campbell, Mel ; Lam, Kit ; Luciw, Paul A ; Tepper, Clifford G ; Kung, Hsing-Jien. / Histone demethylase JMJD2A regulates Kaposi's sarcoma-associated herpesvirus replication and is targeted by a viral transcriptional factor. In: Journal of Virology. 2011 ; Vol. 85, No. 7. pp. 3283-3293.
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AU - Izumiya, Yoshihiro

AU - Wu, Chun Yi

AU - Hsieh, Wen Ping

AU - Lin, Su Fang

AU - Campbell, Mel

AU - Lam, Kit

AU - Luciw, Paul A

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AU - Kung, Hsing-Jien

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