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The Integrator complex is required for optimal lytic lifecycle of Kaposi’s Sarcoma-Associated Herpesvirus [ChIP-seq]

ABSTRACT: The Integrator complex (INT) is an essential regulator of RNA biogenesis across evolution. Most current findings describe INT’s function in states of equilibrium, presenting a research gap in INT’s role in dynamic states, such as in infections and cancers. Viruses hijack cellular RNA machinery to transcribe their genes and produce viral progeny, presenting a unique condition to investigate INT-dependent RNA regulation under perturbation. Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic DNA virus that causes two deadly cancers, Kaposi’s sarcoma and primary effusion lymphoma. KSHV undergoes a highly regulated and robust transcription of viral genes upon lytic reactivation, providing a complex and dynamic system to investigate Integrator-mediated viral/host RNA metabolism. We find that Integrator subunit 11 (INTS11), the enzymatic core of INT, is required for an optimal KSHV lytic lifecycle following reactivation from latency or after primary infection. While INTS11 knockdown’s impact on the human transcriptome remains bi-directional, it almost exclusively represses the KSHV transcriptome throughout the lytic stages. This inhibits viral protein expression, viral genome replication, and virion production. Integrator subunits 9 and 6 are also important for the KSHV lytic lifecycle. RNA-seq analyses revealed dynamic and unique signatures of human transcriptomes during each latent or lytic stage. Mechanistically, ChIP-seq analysis showed that INTS11 is broadly and increasingly recruited to the KSHV genome with unique binding site specificities as the lytic cycle progresses, suggesting that KSHV hijacks INTS11 to facilitate its lytic lifecycle. These findings reveal unexpected and critical roles of the Integrator complex in the lytic phase of KSHV infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300544 | GEO | 2025/06/25

REPOSITORIES: GEO

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Project description:Enhancers play indispensable roles in cell proliferation and survival through spatiotemporally regulating gene transcription. In addition, active enhancers and super-enhancers often produce noncoding enhancer RNAs (eRNAs) that precisely control RNA polymerase II activity. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human oncogenic gamma-2 herpesvirus that causes Kaposi’s sarcoma and lymphoproliferative diseases of B-cell origin such as primary effusion lymphoma (PEL). It is well characterized that KSHV utilizes host epigenetic and nuclear machineries to control the switch between two life cycles, latency and lytic replication. However, how KSHV impacts the host epigenome at different stages of viral life cycle is not well understood. Using the analysis of global run-on sequencing (GRO-seq) and chromatin-immunoprecipitation sequencing (ChIP-seq), we profiled the dynamics of host transcriptional regulatory elements during latency and lytic replication of KSHV-infected PEL cells. This study showed that a number of critical host genes for KSHV latency, including MYC proto-oncogene, were under the control of super-enhancers and eRNAs that were globally repressed upon viral reactivation. A combination of circular chromosome conformation capture combined with sequencing (4C-seq), GRO-seq and ChIP-seq indicated that the eRNA-expressing super-enhance regions were located at downstream of the MYC gene in KSHV-infected PELs. Treatment of an epigenetic drug to block enhancer function or shRNA-mediated depletion of the eRNA expression significantly reduced MYC mRNA expression in KSHV-infected PELs. Finally, while cellular IRF4 acted upon the eRNAs and super-enhancers for MYC expression during latency, the KSHV viral IRF4 repressed cellular IRF4 expression upon reactivation, decreasing MYC expression and thereby, facilitating lytic replication. Taken together, these data suggest that KSHV acts as an epigenetic driver that modifies host epigenomic status by effectively regulating enhancer function upon reactivation.

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The Integrator complex is required for optimal lytic lifecycle of Kaposi’s Sarcoma-Associated Herpesvirus [ChIP-seq]

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