PAN's Labyrinth: Molecular biology of Kaposi's sarcoma-associated herpesvirus (KSHV) PAN RNA, a multifunctional long noncoding RNA

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesivrus, the causative agent of Kaposi's sarcoma and body cavity lymphomas. During infection KSHV produces a highly abundant long non-coding polyadenylated RNA that is retained in the nucleus known as PAN RNA. Long noncoding RNAs (lncRNA) are key regulators of gene expression and are known to interact with specific chromatin modification complexes, working in cis and trans to regulate gene expression. Data strongly supports a model where PAN RNA is a multifunctional regulatory transcript that controls KSHV gene expression by mediating the modification of chromatin by targeting the KSHV repressed genome.

Figure 1

Schematic diagram depicting key features of the PAN locus and transcript. (A) The nucleotide numbering for the K7 ORF and PAN transcript corresponds to genbank accession number U75698.1 for HHV8/KSHV genome type M isolated from BC-1 cells. The numbering for the RRE within the PAN promoter and the ENE is from the transcription start site; (B) The secondary structure of the ENE and MRE sequence within PAN RNA to prevent degradation and increase stability.

Figure 2

PAN RNA both activates and represses gene expression depending on its interaction with chromatin modifying complexes. (A) The interaction of PAN RNA with LANA during reactivation is partly responsible for the LANA-episome dissociation allowing for the expression of lytic transcripts. In this model PAN RNA acts as a “sponge” to keep LANA from repressing viral gene expression; (B) The interaction of PAN RNA with UTX/JMJD3 targets H3K37 for demethylation and acts to increase gene expression. The interaction of PAN RNA with viral encoded processivity factor ORF59 may aid in the targeting UTX/JMJD3 to viral genes during lytic gene expression; (C) PAN RNA’s interaction with PRC2 targets H3K27 for methylation and acts to repress gene expression. The mechanism for specific targeting of PAN RNA is currently under investigation.