| 概要： |
KSHV has been linked to Kaposi’s sarcoma (KS) as well as primary effusion lymphoma (PEL or body-cavity B-lymphoma [BCBL]), and a subset of multicentric Castleman’s disease. Like other herpesviruses, KSHV has two distinguished life styles. One is latent infection, in which the expression of most viral genes is shut-down, and the other is lytic replication, in which 80+ genes are robustly expressed. Viral chromatin remodeling is tightly linked to the transcriptional states of herpesvirus genomes and is considered to be a key step in the transition from latent infection to lytic replication and vice-versa. During latent infection all but a few viral genes such as LANA (ORF73), which is involved in viral latency and/or cell transformation, are silenced. LANA is the essential factor for establishing KSHV latency by silencing the viral genome, in addition to maintaining KSHV episomes in infected cells. It is largely accepted that epigenetic gene regulation plays an important role in latency establishment; however its exact contribution and mechanistic details pertaining to latency remain to be explored.
Accumulating evidence supports the idea that epigenetic gene regulation is of equal importance as a causative factor for cancer progression as has been ascribed to genetic mutations. Our studies demonstrate that expression of the latent protein, LANA, completely silences the cellular INK4b-ARF-INK4a locus, which encodes for two cyclin-dependent kinase inhibitors, p15(INK4b) and p16(INK4a) and a regulator of the p53 pathway, ARF. Accordingly, silencing of tumor suppressors by LANA led to cellular transformation in presence of oncogenic stimuli. Subsequent studies with genomic tiling arrays identified that LANA is recruited to the INK4b/INK4a genomic locus in KSHV naturally-infected cells and increased local SUMO (Small ubiquitin-like modifier) concentration. Finally, biochemical studies showed that KSHV LANA was able to enhance conjugation of SUMO on histones, indicating KSHV LANA is a histone targeting SUMO ligase. In conjunction with our previous publication, which showed that KSHV immediate early protein, K-Rta, is a SUMO-targeting ubiquitin ligase, KSHV may generate unique strategy to “hijack” cellular SUMO pathways to control gene expression.
Perhaps the most exciting new development of epigenetic regulation of transcriptional programs by histone targeting enzymes is the recent findings that (long non-coding) lncRNA, previously thought to be “transcription noise”, interact with those enzymes to modulate their functions. Non-coding (nc)RNAs are mainly classified as housekeeping or regulatory ncRNA, and based on transcript size, regulatory ncRNA can be further grouped into two subclasses; small non-coding RNA (20-200 nt) and long non-coding RNA (IncRNA, >200 nt). Although the role of small regulatory RNAs (microRNAs and siRNAs [small interfering RNA]) in gene silencing is well defined, the biological function of lncRNA has just begun to be explored.
Like proteins, diverse biological functions of lncRNAs have been identified/proposed, including the integrity of the nuclear structure, regulation of gene expression, chromatin remodeling, transcription, and posttranscriptional processing. Accordingly, cellular lncRNA has been shown to be associated with critical biological processes such as cell differentiation, development, and cancer progression.
In addition to viral proteins, viral non-coding RNA was found to form unique transcriptional complexes with viral proteins as well as with cellular polycomb repressor complex 2 (PRC2), which regulates both host and viral gene expression in an epigenetic manner. Both viral repressor and cellular repressive PRC2 complexes are sequestered away from the KSHV genome in the presence of viral non-coding RNA. This mechanism may provide a favorable environment for lytic gene expression. |
