Coordination of KSHV Latent and Lytic Gene Control by CTCF-Cohesin Mediated Chromosome Conformation

PLoS Pathogens

Andreas Wiedmer¹  Erle Robertson²  Paul M. Lieberman³  Yan Yuan⁴  Hyojeung Kang⁴ 

[1] The Kyungpook National University, College of Pharmacy, Daegu, Korea;The University of Pennsylvania, School of Dentistry, Philadelphia, Pennsylvania, United States of America;The University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, United States of America;The Wistar Institute, Philadelphia, Pennsylvania, United States of America

关键词: Polymerase chain reaction;    Chromatin;    Gene expression;    Viral persistence;    latency;    Gene regulation;    Kaposi's sarcoma-associated herpesvirus;    Cell cycle;    cell division;    293T cells;   

DOI  :  10.1371/journal.ppat.1002140

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Herpesvirus persistence requires a dynamic balance between latent and lytic cycle gene expression, but how this balance is maintained remains enigmatic. We have previously shown that the Kaposi's Sarcoma-Associated Herpesvirus (KSHV) major latency transcripts encoding LANA, vCyclin, vFLIP, v-miRNAs, and Kaposin are regulated, in part, by a chromatin organizing element that binds CTCF and cohesins. Using viral genome-wide chromatin conformation capture (3C) methods, we now show that KSHV latency control region is physically linked to the promoter regulatory region for ORF50, which encodes the KSHV immediate early protein RTA. Other linkages were also observed, including an interaction between the 5′ and 3′ end of the latency transcription cluster. Mutation of the CTCF-cohesin binding site reduced or eliminated the chromatin conformation linkages, and deregulated viral transcription and genome copy number control. siRNA depletion of CTCF or cohesin subunits also disrupted chromosomal linkages and deregulated viral latent and lytic gene transcription. Furthermore, the linkage between the latent and lytic control region was subject to cell cycle fluctuation and disrupted during lytic cycle reactivation, suggesting that these interactions are dynamic and regulatory. Our findings indicate that KSHV genomes are organized into chromatin loops mediated by CTCF and cohesin interactions, and that these inter-chromosomal linkages coordinate latent and lytic gene control.

【 授权许可】

CC BY