Decision letter: HIV Tat controls RNA Polymerase II and the epigenetic landscape to transcriptionally reprogram target immune cells

AbstractMutations in lamin A have been reported to be associated with over 16 human diseases including dilated cardiomyopathy (DCM). We have focused on three such DCM causing mutants of lamin A which have to address the contribution of lamins in the pathogenesis of DCM at molecular level. We have elucidated the effect of these mutants for the first time on the epigenetic landscape of a myogenic fibroblast cell line C2C12. C2C12 cells expressing these mutant proteins exhibited alterations in some histone modification marks like H3K4me3, H3K9me3, H3K27me3, H3K36me3 and RNA Polymerase II activity compared to its wild type variants. This report paves the way for further studies involving epigenetic regulation in laminopathies which would be an important step in explaining the molecular mechanism and pathophysiology of the diseases like dilated cardiomyopathy.High Lightslamin A K97E mutation predominantly alters H3K9me3 histone modifications landscapelamin A K97E aggregates within nucleus also sequester the HP1γlamin A K97E mutation affects RNA polymerase II distribution pattern

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HIV Tat controls RNA Polymerase II and the epigenetic landscape to transcriptionally reprogram target immune cells

eLife ◽

10.7554/elife.08955 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 24

Author(s):

Jonathan E Reeder ◽

Youn-Tae Kwak ◽

Ryan P McNamara ◽

Christian V Forst ◽

Iván D'Orso

Keyword(s):

Rna Polymerase ◽

Rna Polymerase Ii ◽

Immune Cells ◽

Rna Structure ◽

Molecular Mechanisms ◽

Target Genes ◽

Regulatory Mechanisms ◽

Messenger Rnas ◽

Transcriptional Regulatory Mechanisms ◽

Cellular Transcription

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.

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The Cdk9 and cyclin T subunits of TAK/P-TEFb localize to splicing factor-rich nuclear speckle regions

Journal of Cell Science ◽

10.1242/jcs.114.8.1491 ◽

2001 ◽

Vol 114 (8) ◽

pp. 1491-1503 ◽

Cited By ~ 3

Author(s):

C.H. Herrmann ◽

M.A. Mancini

Keyword(s):

Rna Polymerase ◽

Rna Polymerase Ii ◽

Elongation Factor ◽

Tat Protein ◽

Nuclear Speckles ◽

Cyclin T1 ◽

Transcription Inhibitors ◽

Hiv Tat ◽

Cellular Cofactor ◽

A Site

TAK/P-TEFb is an elongation factor for RNA polymerase II-directed transcription that is thought to function by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. TAK/P-TEFb is composed of Cdk9 and cyclin T and serves as the cellular cofactor for the human immunodeficiency virus transactivator Tat protein. In this study, we examined the subcellular distribution of Cdk9 and cyclin T1 using high resolution immunofluorescence microscopy and found that Cdk9 and cyclin T1 localized throughout the non-nucleolar nucleoplasm, with increased signal present at numerous foci. Both Cdk9 and cyclin T1 showed only limited colocalization with different phosphorylated forms of RNA polymerase II. However, significant colocalization with antibodies to several splicing factors that identify nuclear ‘speckles’ was observed for Cdk9 and especially for cyclin T1. The pattern of Cdk9 and cyclin T1 distribution was altered in cells treated with transcription inhibitors. Transient expression of cyclin T1 deletion mutants indicated that a region in the central portion of cyclin T1 is important for accumulation at speckles. Furthermore, cyclin T1 proteins that accumulated at speckles were capable of recruiting Cdk9 and the HIV Tat protein to this compartment in overexpression experiments. These results suggest that cyclin T1 functions to recruit its binding partners to nuclear speckles and raises the possibility that nuclear speckles are a site of TAK/P-TEFb function.

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Nutrient-regulated gene expression in eukaryotes

Biochemical Society Symposium ◽

10.1042/bss0730085 ◽

2006 ◽

Vol 73 ◽

pp. 85-96 ◽

Cited By ~ 8

Author(s):

Richard J. Reece ◽

Laila Beynon ◽

Stacey Holden ◽

Amanda D. Hughes ◽

Karine Rébora ◽

...

Keyword(s):

Gene Expression ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Transcriptional Control ◽

Direct Interaction ◽

Signalling Pathways ◽

A Cell ◽

One Step ◽

Higher Eukaryotes ◽

Regulated Gene Expression

The recognition of changes in environmental conditions, and the ability to adapt to these changes, is essential for the viability of cells. There are numerous well characterized systems by which the presence or absence of an individual metabolite may be recognized by a cell. However, the recognition of a metabolite is just one step in a process that often results in changes in the expression of whole sets of genes required to respond to that metabolite. In higher eukaryotes, the signalling pathway between metabolite recognition and transcriptional control can be complex. Recent evidence from the relatively simple eukaryote yeast suggests that complex signalling pathways may be circumvented through the direct interaction between individual metabolites and regulators of RNA polymerase II-mediated transcription. Biochemical and structural analyses are beginning to unravel these elegant genetic control elements.

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