Epigenomic regulation of human T-cell leukemia virus by chromatin-insulator CTCF

Cheng, Xiaogang; Joseph, Ancy; Castro, Victor; Chen-Liaw, Alice; Skidmore, Zachary L.; Ueno, Takaharu; Fujisawa, Jun–ichi; Rauch, Daniel A.; Challen, Grant A.; Martinez, Michael P.; Green, Patrick; Griffith, Malachi; Payton, Jacqueline E.; Edwards, John; Ratner, Lee

doi:10.1371/journal.ppat.1009577

Cited by 14 publications

(22 citation statements)

References 74 publications

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“…The viral CTCF-BS (vCTCF-BS) is located at a sharp border in epigenetic modifications within the pX region of the proviral genome (Satou et al, 2016). The presence of the vCTCF-BS disrupts host chromatin structure and looping, regulates viral mRNA splicing, and maintains/regulates the epigenetic barrier found in the pX region (Melamed et al, 2018;Cheng et al, 2021). However, loss of the vCTCF-BS did not disrupt the ability of the virus to immortalize target cells in vitro or establish persistence in a rabbit model of infection (Martinez et al, 2019).…”

Section: Antisense Transcription In Human T-cell Leukemia Virusesmentioning

confidence: 98%

Novel perspectives on antisense transcription in HIV-1, HTLV-1, and HTLV-2

et al. 2022

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The genome of retroviruses contains two promoter elements (called long terminal repeat or LTR) at the 5′ and 3′ end of their genome. Although the expression of retroviral genes generally depends on the promoter located in the 5′ LTR, the 3′ LTR also has promoter activity responsible for producing antisense transcripts. These natural antisense transcripts (NATs) are a class of RNA molecules transcribed from the opposite strand of a protein-coding gene. NATs have been identified in many prokaryotic and eukaryotic systems, as well as in human retroviruses such as human immunodeficiency virus type 1 (HIV-1) and HTLV-1/2 (human T-cell leukemia virus type 1/2). The antisense transcripts of HIV-1, HTLV-1, and HTLV-2 have been briefly characterized over the past several years. However, a complete appreciation of the role these transcripts play in the virus lifecycle and the cellular factors which regulate their transcription is still lacking. This review provides an overview of antisense transcription in human retroviruses with a specific focus on the MEF-2 family of transcription factors, the function(s) of the antisense protein products, and the application of antisense transcription models in therapeutics against HIV-1 and HTLV-1 in the context of co-infection.

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Section: Antisense Transcription In Human T-cell Leukemia Virusesmentioning

confidence: 98%

Novel perspectives on antisense transcription in HIV-1, HTLV-1, and HTLV-2

et al. 2022

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“…CTCF-binding sequences on the provirus suggest a new relationship between the provirus and host epigenome [ 23 ]. Some studies have shown that HTLV-1 disrupts the host chromatin structure by forming a loop between the provirus and the host genome, and the loop depends on the critical chromatin architectural protein CTCF [ 23 , 24 , 25 , 26 ]. Although it remains unclear how these changes contribute to the characteristics of infected cells, clonal structure, and pathogenesis of ATL, the impact of such insertional mutagenesis on the host epigenome is an essential insight into the pathogenicity of HTLV-1.…”

Section: Early Formation Of Epigenomic Abnormalities In Infected Cell...mentioning

confidence: 99%

Clonal Selection and Evolution of HTLV-1-Infected Cells Driven by Genetic and Epigenetic Alteration

Yamagishi

Suzuki

Watanabe

et al. 2022

Viruses

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T cells infected with human T-cell leukemia virus type 1 (HTLV-1) acquire various abnormalities during a long latent period and transform into highly malignant adult T-cell leukemia-lymphoma (ATL) cells. This can be described as “clonal evolution”, in which a single clone evolves into ATL cells after overcoming various selective pressures in the body of the infected individuals. Many studies have shown that the genome and epigenome contain a variety of abnormalities, which are reflected in gene expression patterns and define the characteristics of the disease. The latest research findings suggest that epigenomic disorders are thought to begin forming early in infection and evolve into ATL through further changes and accentuation as they progress. Genomic abnormalities profoundly affect clonal dominance and tumor cell characteristics in later events. ATL harbors both genomic and epigenomic abnormalities, and an accurate understanding of these can be expected to provide therapeutic opportunities.

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“…In HTLV-1 infected cell lines and primary malignant cells from ATL patients, the 5′LTR (as L.545), but not the 3′ LTR, of provirus are highly methylated (117, 118). Recently, a suppressive regulation of HTLV-1 gene expression by CTCF was also reported (119,120). However, the mechanism of why all HTLV-1-infected cells uniformly switch to full transcriptional latency within a certain period is not known.…”

Section: Regulation Of Viral Gene Expression During Latent Infectionmentioning

confidence: 99%

Tuning Rex rules HTLV-1 pathogenesis

Nakano

Watanabe

2022

Front. Immunol.

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HTLV-1 is an oncovirus causing ATL and other inflammatory diseases such as HAM/TSP and HU in about 5% of infected individuals. It is also known that HTLV-1-infected cells maintain a disease-free, immortalized, latent state throughout the lifetimes of about 95% of infected individuals. We believe that the stable maintenance of disease-free infected cells in the carrier is an intrinsic characteristic of HTLV-1 that has been acquired during its evolution in the human life cycle. We speculate that the pathogenesis of the virus is ruled by the orchestrated functions of viral proteins. In particular, the regulation of Rex, the conductor of viral replication rate, is expected to be closely related to the viral program in the early active viral replication followed by the stable latency in HTLV-1 infected T cells. HTLV-1 and HIV-1 belong to the family Retroviridae and share the same tropism, e.g., human CD4+ T cells. These viruses show significant similarities in the viral genomic structure and the molecular mechanism of the replication cycle. However, HTLV-1 and HIV-1 infected T cells show different phenotypes, especially in the level of virion production. We speculate that how the activity of HTLV-1 Rex and its counterpart HIV-1 Rev are regulated may be closely related to the properties of respective infected T cells. In this review, we compare various pathological aspects of HTLV-1 and HIV-1. In particular, we investigated the presence or absence of a virally encoded “regulatory valve” for HTLV-1 Rex or HIV-1 Rev to explore its importance in the regulation of viral particle production in infected T cells. Finally, wereaffirm Rex as the key conductor for viral replication and viral pathogenesis based on our recent study on the novel functional aspects of Rex. Since the activity of Rex is closely related to the viral replication rate, we hypothesize that the “regulatory valve” on the Rex activity may have been selectively evolved to achieve the “scenario” with early viral particle production and the subsequent long, stable deep latency in HTLV-1 infected cells.

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Epigenomic regulation of human T-cell leukemia virus by chromatin-insulator CTCF

Cited by 14 publications

References 74 publications

Novel perspectives on antisense transcription in HIV-1, HTLV-1, and HTLV-2

Novel perspectives on antisense transcription in HIV-1, HTLV-1, and HTLV-2

Clonal Selection and Evolution of HTLV-1-Infected Cells Driven by Genetic and Epigenetic Alteration

Tuning Rex rules HTLV-1 pathogenesis

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