title: Negative elongation factor (NELF) coordinates RNA polymerase II pausing, premature termination, and chromatin remodeling to regulate HIV transcription.
abstract: A barrier to eradicating HIV infection is targeting and eliminating latently infected cells. Events that contribute to HIV transcriptional latency include repressive chromatin structure, transcriptional interference, the inability of Tat to recruit positive transcription factor b, and poor processivity of RNA polymerase II (RNAP II). In this study, we investigated mechanisms by which negative elongation factor (NELF) establishes and maintains HIV latency. Negative elongation factor (NELF) induces RNAP II promoter proximal pausing and limits provirus expression in HIV-infected primary CD4(+) T cells. Decreasing NELF expression overcomes RNAP II pausing to enhance HIV transcription elongation in infected primary T cells, demonstrating the importance of pausing in repressing HIV transcription. We also show that RNAP II pausing is coupled to premature transcription termination and chromatin remodeling. NELF interacts with Pcf11, a transcription termination factor, and diminishing Pcf11 in primary CD4(+) T cells induces HIV transcription elongation. In addition, we identify NCoR1-GPS2-HDAC3 as a NELF-interacting corepressor complex that is associated with repressed HIV long terminal repeats. We propose a model in which NELF recruits Pcf11 and NCoR1-GPS2-HDAC3 to paused RNAP II, reinforcing repression of HIV transcription and establishing a critical checkpoint for HIV transcription and latency.
authors.affiliation: From the Immunology and Infectious Diseases, Integrated Biosciences Graduate Program, Penn State University, University Park, Pennsylvania 16802,; the Departments of Medicine and Infectious Diseases.
authors.forename: Malini
authors.initials: M
authors.lastname: Natarajan
authors.affiliation: the Departments of Medicine and Infectious Diseases.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Schiralli Lester
authors.affiliation: the Departments of Medicine and Infectious Diseases.
authors.forename: Chanhyo
authors.initials: C
authors.lastname: Lee
authors.affiliation: the Department of Biochemistry and Molecular Biology, Penn State University, University Park, Pennsylvania 16802.
authors.forename: Anamika
authors.initials: A
authors.lastname: Missra
authors.affiliation: Microbiology, and.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasserman
authors.affiliation: Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118 and.
authors.forename: Martin
authors.initials: M
authors.lastname: Steffen
authors.affiliation: the Department of Biochemistry and Molecular Biology, Penn State University, University Park, Pennsylvania 16802.
authors.forename: David S
authors.initials: DS
authors.lastname: Gilmour
authors.affiliation: the Departments of Medicine and Infectious Diseases,; Microbiology, and. Electronic address: andrew.henderson@bmc.org.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Henderson
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D042002:Chromatin Assembly and Disassembly; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008954:Models, Biological; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D061805:Transcription Elongation, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D061806:Transcription Termination, Genetic; D017735:Virus Latency / Q000502:physiology; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D047908:Intracellular Signaling Peptides and Proteins; D056971:Nuclear Receptor Co-Repressor 1; D012319:RNA Polymerase II; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors; D000099186:Histone Deacetylase 3; C103316:GPS2 protein, human; C539127:NCOR1 protein, human; C411985:NSMF protein, human; C521949:Pcf11 protein, human
keywords: HIV; RNA Polymerase II; Transcription Elongation Factors; Transcription Regulation; Transcription Repressor