Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Latency-Associated Nuclear Antigen Regulates the KSHV Epigenome by Association with the Histone Demethylase KDM3A

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

doi:10.1128/jvi.00011-13

Cited by 58 publications

(62 citation statements)

References 65 publications

(52 reference statements)

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“…The majority of the KSHV genome is silenced during latency through multiple epigenetic modifications, such as histone deacetylation and repressive histone methylations. During reactivation, the levels of histone acetylation increase, while repressive histone methylation marks are removed from the viral genome and replaced with activating histone methylation marks (9,10,26,27). In a pilot study, we observed that SCFA stimulation of BCBL1 cells not only increased the overall levels of acetylated histone marks, such as H4K12-Ac and H2B-Ac, but also decreased the levels of the constitutive repressive histone trimethylation mark H3K9Me3 and the facultative repressive histone trimethylation mark H3K27Me3 (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…During latency, the majority of the KSHV genome is silenced through multiple epigenetic regulatory mechanisms, including histone deacetylation, repressive histone methylation (9,45,46), DNA methylation (26,47), and repression of specific chromatin regions by the insulator CCCTC-binding factor (CTCF) and the cohesin complex, among others (48)(49)(50). Reactivation of the latent virus for lytic replication may require removal of all of the silencing factors and addition of chromatin-activating elements to the viral genomes simultaneously.…”

Section: Discussionmentioning

confidence: 99%

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Short-Chain Fatty Acids from Periodontal Pathogens Suppress Histone Deacetylases, EZH2, and SUV39H1 To Promote Kaposi's Sarcoma-Associated Herpesvirus Replication

Shahir

Sha

et al. 2014

J Virol

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Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS). IMPORTANCE About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known ifthe oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Short-Chain Fatty Acids from Periodontal Pathogens Suppress Histone Deacetylases, EZH2, and SUV39H1 To Promote Kaposi's Sarcoma-Associated Herpesvirus Replication

Shahir

Sha

et al. 2014

J Virol

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“…Previously, we performed a large-scale coimmunoprecipitation (co-IP) analysis to identify latency-associated nuclear antigen (LANA)-interacting protein partners using stably LANA-expressing HeLa cells (11). In the experiment, RNA-binding factors such as hnRNPs, SF3B1, THRAP3, and DHX15 were found to be among LANA-interacting proteins.…”

mentioning

confidence: 99%

A Lytic Viral Long Noncoding RNA Modulates the Function of a Latent Protein

Campbell

Kim

Chang³

et al. 2014

J Virol

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Latent Kaposi's sarcoma-associated herpesvirus (KSHV) episomes are coated with viral latency-associated nuclear antigen (LANA). In contrast, LANA rapidly disassociates from episomes during reactivation. Lytic KSHV expresses polyadenylated nuclear RNA (PAN RNA), a long noncoding RNA (lncRNA). We report that PAN RNA promotes LANA-episome disassociation through an interaction with LANA which facilitates LANA sequestration away from KSHV episomes during reactivation. These findings suggest that KSHV may have evolved an RNA aptamer to regulate latent protein function. Kaposi's sarcoma-associated herpesvirus (KSHV; also called human herpesvirus 8) is a gammaherpesvirus linked to Kaposi's sarcoma (KS) and two lymphoproliferative disorders, primary effusion lymphoma (PEL; also called body cavity B lymphoma [BCBL]) and a subset of multicentric Castleman's disease (1). Pervasive transcription, which generates a wide variety of transcripts with little apparent protein-coding potential, has been observed on a genome-wide scale in beta-and gammaherpesviruses, including human cytomegalovirus (HCMV) (2) and KSHV (3, 4), during lytic growth. One class of noncoding RNAs, called long noncoding RNAs (lncRNAs), are defined as RNA polymerase II (Pol II)-transcribed noncoding RNAs greater than 200 nucleotides in length (5). KSHV encodes a viral lncRNA known as polyadenylated nuclear RNA (PAN RNA), an abundant early gene product. Although PAN RNA was first described 17 years ago (6), its discovery predated the widespread recognition of noncoding RNAs. However, recent studies have begun to focus on the role of PAN RNA in the KSHV life cycle. PAN RNA has been reported to play a role in KSHV gene expression, replication, and immune modulation (7-9). PAN RNA binds the transcription factor IRF4 (8), lysine demethylases UTX and JMJD3, and the lysine methyltransferase MLL2 (9), in support of the notion that, similar to cellular lncRNAs, PAN RNA interacts with transcriptional regulators and chromatin modifiers to modulate viral gene expression. Moreover, recent mapping studies have found widespread PAN RNA interaction sites on the KSHV episome as well as the host genome, and PAN RNA expression is required for optimal expression of the entire KSHV lytic gene expression program (10).Previously, we performed a large-scale coimmunoprecipitation (co-IP) analysis to identify latency-associated nuclear antigen (LANA)-interacting protein partners using stably LANA-expressing HeLa cells (11). In the experiment, RNA-binding factors such as hnRNPs, SF3B1, THRAP3, and DHX15 were found to be among LANA-interacting proteins. The result raised the questions of whether LANA possesses the property of RNA binding and whether LANA interacts with PAN RNA. To address this, the ability of LANA to interact with PAN RNA was evaluated in vitro and in vivo. In order to perform in vitro interaction analyses, fulllength LANA was expressed using recombinant baculovirus and purified by FLAG-M2 resin (Flag-LANA) (Fig. 1A). Purified Flag-LANA was incubated with PAN RNA that...

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“…LANA is a multifunctional protein; it regulates a variety of cellular activities including gene transcription, DNA replication, and signaling pathways involved in cell proliferation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Kaposi Sarcoma (Ks)mentioning

confidence: 99%

The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence

Tan

Juillard

et al. 2015

Journal of Biological Chemistry

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Background: KSHV LANA binds virus DNA to mediate episome maintenance. Results: Mutating the novel LANA DNA binding domain (DBD) positive electrostatic patch engenders replication and episome persistence deficiencies. Conclusion: The LANA positive patch, possibly acting through a cell partner, is important for episome maintenance. Significance: Strategies that interfere with LANA positive patch function may allow future disruption of KSHV latency.

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Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Latency-Associated Nuclear Antigen Regulates the KSHV Epigenome by Association with the Histone Demethylase KDM3A

Cited by 58 publications

References 65 publications

Short-Chain Fatty Acids from Periodontal Pathogens Suppress Histone Deacetylases, EZH2, and SUV39H1 To Promote Kaposi's Sarcoma-Associated Herpesvirus Replication

Short-Chain Fatty Acids from Periodontal Pathogens Suppress Histone Deacetylases, EZH2, and SUV39H1 To Promote Kaposi's Sarcoma-Associated Herpesvirus Replication

A Lytic Viral Long Noncoding RNA Modulates the Function of a Latent Protein

The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence

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