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The chromatin loop release factor WAPL regulates EBV latency status by restricting LMP production [RNA-seq]

ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous human pathogen that is etiologically linked to several cancers and has been connected to multiple sclerosis. EBV persists in its human hosts through a biphasic replication cycle that depends on three latency stages. Understanding the host mechanisms that contribute to the tight regulation of viral gene expression in the discrete states of latency III, latency II, and latency I is important for developing therapeutic approaches for treating EBV positive cancers. Regulation of the chromatin structure of the EBV genome by cohesin and CTCF plays a role in this latency type switching. However, the function of the cohesin release factor WAPL had not previously been understood. In this study, we employ RNA-seq combined with immunofluorescence analysis to determine that the cohesin release factor WAPL plays a role specifically in inhibiting the expression of the oncogenic latent membrane proteins LMP-1 and LMP-2A. Through a combination of Hi-ChIP and ChIP-qPCR, we uncover that WAPL loss alters the looping interactions within the EBV genome and alters the histone modifications present at the LMP promoter. We propose that EBV coopts WAPL to maintain a latency I state and, without WAPL, leaky expression of the LMP proteins occurs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248336 | GEO | 2024/08/06

REPOSITORIES: GEO

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The chromatin loop release factor WAPL regulates EBV latency status by restricting LMP production [HiChIP]

Project description:Epstein-Barr virus (EBV) is a ubiquitous human pathogen that is etiologically linked to several cancers and has been connected to multiple sclerosis. EBV persists in its human hosts through a biphasic replication cycle that depends on three latency stages. Understanding the host mechanisms that contribute to the tight regulation of viral gene expression in the discrete states of latency III, latency II, and latency I is important for developing therapeutic approaches for treating EBV positive cancers. Regulation of the chromatin structure of the EBV genome by cohesin and CTCF plays a role in this latency type switching. However, the function of the cohesin release factor WAPL had not previously been understood. In this study, we employ RNA-seq combined with immunofluorescence analysis to determine that the cohesin release factor WAPL plays a role specifically in inhibiting the expression of the oncogenic latent membrane proteins LMP-1 and LMP-2A. Through a combination of Hi-ChIP and ChIP-qPCR, we uncover that WAPL loss alters the looping interactions within the EBV genome and alters the histone modifications present at the LMP promoter. We propose that EBV coopts WAPL to maintain a latency I state and, without WAPL, leaky expression of the LMP proteins occurs.

2024-08-06 | GSE248335 | GEO

The chromatin loop release factor WAPL regulates EBV latency status by restricting LMP production

Project description:Epstein-Barr virus (EBV) is a ubiquitous human pathogen that is etiologically linked to several cancers and has been connected to multiple sclerosis. EBV employs a series of latency programs, including latency III, latency II, and latency I, to persistently colonize the B-cell compartment. Each of these programs is associated with human malignancies. However, our understanding remains incomplete of how these distinct latency programs are epigenetically restricted. While regulation of the chromatin structure of the EBV genome by cohesin and CTCF contributes to genome regulation, the function of the cohesin release factor Wings Apart-Like Protein Homolog (WAPL) had not previously been understood. In this study, we employ RNA-seq combined with immunofluorescence analysis to determine that loss of WAPL leads to aberrant expression of the oncogenic latent membrane proteins LMP1 and LMP2A in latency I Burkitt lymphoma cells. Through a combination of Hi-C, Hi-ChIP, and ChIP-qPCR, we uncover that WAPL loss causes alterations in looping across the EBV genome and specifically induces formation of loops between the LMP promoter and the oriLyt enhancers. We propose that EBV coopts WAPL to maintain a strict latency I state and, without WAPL, leaky expression of the LMP proteins occurs.

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Wapl controls higher-order chromatin structure in interphase chromosomes (gene expression)

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Scc2 counteracts a Wapl-independent mechanism that releases cohesin from chromosomes during G1

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The cohesin release factor WAPL restricts chromatin loop extension [ESS]

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