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1.
Mol Cell ; 61(1): 39-53, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26725010

RESUMO

The transition from transcription initiation to elongation at promoters of primary response genes (PRGs) in metazoan cells is controlled by inducible transcription factors, which utilize P-TEFb to phosphorylate RNA polymerase II (Pol II) in response to stimuli. Prior to stimulation, a fraction of P-TEFb is recruited to promoter-proximal regions in a catalytically inactive state bound to the 7SK small nuclear ribonucleoprotein (snRNP) complex. However, it remains unclear how and why the 7SK snRNP is assembled at these sites. Here we report that the transcriptional regulator KAP1 continuously tethers the 7SK snRNP to PRG promoters to facilitate P-TEFb recruitment and productive elongation in response to stimulation. Remarkably, besides PRGs, genome-wide studies revealed that KAP1 and 7SK snRNP co-occupy most promoter-proximal regions containing paused Pol II. Collectively, we provide evidence of an unprecedented mechanism controlling 7SK snRNP delivery to promoter-proximal regions to facilitate "on-site" P-TEFb activation and Pol II elongation.


Assuntos
Regulação Viral da Expressão Gênica , HIV/metabolismo , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , Proteínas Repressoras/metabolismo , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Elongação da Transcrição Genética , Sítios de Ligação , Ativação Enzimática , Células HCT116 , Células HEK293 , HIV/genética , Humanos , Células Jurkat , Complexos Multiproteicos , Fator B de Elongação Transcricional Positiva/metabolismo , Interferência de RNA , RNA Polimerase II/genética , Proteínas Repressoras/genética , Ribonucleoproteínas Nucleares Pequenas/genética , Fatores de Tempo , Transfecção , Proteína 28 com Motivo Tripartido , Ativação Viral
2.
Genom Data ; 7: 250-5, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26981421

RESUMO

The transition of RNA polymerase II (Pol II) from transcription initiation into productive elongation in eukaryotic cells is regulated by the P-TEFb kinase, which phosphorylates the C-terminal domain of paused Pol II at promoter-proximal regions. Our recent study found that P-TEFb (in an inhibited state bound to the 7SK snRNP complex) interacts with the KAP1/TRIM28 transcriptional regulator, and that KAP1 and the 7SK snRNP co-occupy most gene promoters containing paused Pol II. Here we provide a detailed experimental description and analysis of the ChIP-seq datasets that have been deposited into Gene Expression Omnibus (GEO): GS72622, so that independent groups can replicate and expand upon these findings. We propose these datasets would provide valuable information for researchers studying mechanisms of transcriptional regulation including Pol II pausing and pause release.

3.
Elife ; 42015 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-26488441

RESUMO

HIV encodes Tat, a small protein that facilitates viral transcription by binding an RNA structure (trans-activating RNA [TAR]) formed on nascent viral pre-messenger RNAs. Besides this well-characterized mechanism, Tat appears to modulate cellular transcription, but the target genes and molecular mechanisms remain poorly understood. We report here that Tat uses unexpected regulatory mechanisms to reprogram target immune cells to promote viral replication and rewire pathways beneficial for the virus. Tat functions through master transcriptional regulators bound at promoters and enhancers, rather than through cellular 'TAR-like' motifs, to both activate and repress gene sets sharing common functional annotations. Despite the complexity of transcriptional regulatory mechanisms in the cell, Tat precisely controls RNA polymerase II recruitment and pause release to fine-tune the initiation and elongation steps in target genes. We propose that a virus with a limited coding capacity has optimized its genome by evolving a small but 'multitasking' protein to simultaneously control viral and cellular transcription.


Assuntos
Epigênese Genética , HIV/fisiologia , Interações Hospedeiro-Patógeno , RNA Polimerase II/metabolismo , Transcrição Gênica , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , Regulação da Expressão Gênica , Humanos
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