Structural Insights into Acetylated-Histone H4 Recognition by the Bromodomain-PHD Finger Module of Human Transcriptional Coactivator CBP

The transcriptional coactivator BRD4 has a fundamental role in transcription regulation and thus became a promising epigenetic therapeutic candidate to target diverse pathologies. However, the regulation of BRD4 by posttranslational modifications has been largely unexplored. Here, we show that BRD4 is methylated on chromatin at lysine-99 by the protein lysine methyltransferase SETD6. BRD4 methylation negatively regulates the expression of genes that are involved in translation and inhibits total mRNA translation in cells. Mechanistically, we provide evidence that supports a model where BRD4 methylation by SETD6 does not have a direct role in the association with acetylated histone H4 at chromatin. However, this methylation specifically determines the recruitment of the transcription factor E2F1 to selected target genes that are involved in mRNA translation. Together, our findings reveal a previously unknown molecular mechanism for BRD4 methylation–dependent gene-specific targeting, which may serve as a new direction for the development of therapeutic applications.

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Faculty Opinions recommendation of Prognostic significance of the therapeutic targets histone deacetylase 1, 2, 6 and acetylated histone H4 in cutaneous T-cell lymphoma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1160588.620958 ◽

2009 ◽

Author(s):

Janine Wechsler ◽

Dimitri Salameire

Keyword(s):

T Cell ◽

Histone Deacetylase ◽

Cell Lymphoma ◽

Prognostic Significance ◽

Therapeutic Targets ◽

T Cell Lymphoma ◽

Cutaneous T Cell Lymphoma ◽

Histone H4 ◽

Histone Deacetylase 1 ◽

Acetylated Histone H4

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Antiproliferative effects of TSA, PXD‑101 and MS‑275 in A2780 and MCF7 cells: Acetylated histone H4 and acetylated tubulin as markers for HDACi potency and selectivity

Oncology Reports ◽

10.3892/or.2017.6015 ◽

2017 ◽

Author(s):

Vasilis Androutsopoulos ◽

Demetrios Spandidos

Keyword(s):

Histone H4 ◽

Mcf7 Cells ◽

Antiproliferative Effects ◽

Acetylated Tubulin ◽

Acetylated Histone H4

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Active transgenes in zebrafish are enriched in acetylated histone H4 and dynamically associate with RNA Pol II and splicing complexes

Journal of Cell Science ◽

10.1242/jcs.112.7.1045 ◽

1999 ◽

Vol 112 (7) ◽

pp. 1045-1054 ◽

Cited By ~ 1

Author(s):

P. Collas ◽

M.R. Liang ◽

M. Vincent ◽

P. Alestrom

Keyword(s):

Transgene Expression ◽

Functional Organization ◽

Histone Deacetylation ◽

Splicing Factors ◽

Histone H4 ◽

Rna Pol Ii ◽

Pol Ii ◽

Acetylated Histone H4 ◽

Co Precipitation

We have investigated the functional organization of active and silent integrated luciferase transgenes in zebrafish, with the aim of accounting for the variegation of transgene expression in this species. We demonstrate the enrichment of transcriptionally active transgenes in acetylated histone H4 and the dynamic association of the transgenes with splicing factor SC35 and RNA Pol II. Analysis of interphase nuclei and extended chromatin fibers by immunofluorescence and in situ hybridization reveals a co-localization of transgenes with acetylated H4 in luciferase-expressing animals only. Enrichment of expressed transgenes in acetylated H4 is further demonstrated by their co-precipitation from chromatin using anti-acetylated H4 antibodies. Little correlation exists, however, between the level of histone acetylation and the degree of transgene expression. In transgene-expressing zebrafish, most transgenes co-localize with Pol II and SC35, whereas no such association occurs in non-expressing individuals. Inhibition of Pol II abolishes transgene expression and disrupts association of transgenes with SC35, although inactivated transgenes remains enriched in acetylated histones. Exposure of embryos to the histone deacetylation inhibitor TSA induces expression of most silent transgenes. Chromatin containing activated transgenes becomes enriched in acetylated histones and the transgenes recruit SC35 and Pol II. The results demonstrate a correlation between H4 acetylation and transgene activity, and argue that active transgenes dynamically recruit splicing factors and Pol II. The data also suggest that dissociation of splicing factors from transgenes upon Pol II inhibition is not a consequence of changes in H4 acetylation.

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Reduced Acetylated Histone H4 is Associated With Promoter Methylation of the Fragile Histidine Triad Gene in Resected Esophageal Squamous Cell Carcinoma

The Annals of Thoracic Surgery ◽

10.1016/j.athoracsur.2006.03.066 ◽

2006 ◽

Vol 82 (2) ◽

pp. 396-401 ◽

Cited By ~ 13

Author(s):

Ching Tzao ◽

Guang-Huan Sun ◽

Ho-Jui Tung ◽

Han-Shui Hsu ◽

Wen-Hu Hsu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Promoter Methylation ◽

Histone H4 ◽

Fragile Histidine Triad ◽

Acetylated Histone H4

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Genome-Wide Relationships between TAF1 and Histone Acetyltransferases in Saccharomyces cerevisiae

Molecular and Cellular Biology ◽

10.1128/mcb.26.7.2791-2802.2006 ◽

2006 ◽

Vol 26 (7) ◽

pp. 2791-2802 ◽

Cited By ~ 36

Author(s):

Melissa Durant ◽

B. Franklin Pugh

Keyword(s):

Gene Expression ◽

Saccharomyces Cerevisiae ◽

Histone Acetylation ◽

Rna Polymerase Ii ◽

Histone Acetyltransferases ◽

Histone H4 ◽

Promoter Regions ◽

Genome Wide ◽

Acetylated Histone H4

ABSTRACT Histone acetylation regulates gene expression, yet the functional contributions of the numerous histone acetyltransferases (HATs) to gene expression and their relationships with each other remain largely unexplored. The central role of the putative HAT-containing TAF1 subunit of TFIID in gene expression raises the fundamental question as to what extent, if any, TAF1 contributes to acetylation in vivo and to what extent it is redundant with other HATs. Our findings herein do not support the basic tenet that TAF1 is a major HAT in Saccharomyces cerevisiae, nor do we find that TAF1 is functionally redundant with other HATs, including Gcn5, Elp3, Hat1, Hpa2, Sas3, and Esa1, which is in contrast to previous conclusions regarding Gcn5. Our findings do reveal that of these HATs, only Gcn5 and Esa1 contribute substantially to gene expression genome wide. Interestingly, histone acetylation at promoter regions throughout the genome does not require TAF1 or RNA polymerase II, indicating that most acetylation is likely to precede transcription and not depend upon it. TAF1 function has been linked to Bdf1, which binds TFIID and acetylated histone H4 tails, but no linkage between TAF1 and the H4 HAT Esa1 has been established. Here, we present evidence for such a linkage through Bdf1.

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Targeted histone H4 acetylation via phosphoinositide 3-kinase- and p70s6-kinase-dependent pathways inhibits iNOS induction in mesangial cells

AJP Renal Physiology ◽

10.1152/ajprenal.00316.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. F496-F502 ◽

Cited By ~ 17

Author(s):

Zhiyuan Yu ◽

Bruce C. Kone

Keyword(s):

Mesangial Cells ◽

Histone H4 ◽

P70s6 Kinase ◽

Inos Gene ◽

Histone H4 Acetylation ◽

Inos Promoter ◽

Acetylated Histone H4 ◽

Phosphoinositide 3 Kinase ◽

Kinase Pathway ◽

Inos Induction

The inducible nitric oxide synthase (iNOS) gene plays an important role in the response to and propagation of injury in glomerular mesangial cells. Although several cis and trans regulatory factors have been characterized, epigenetic regulation of the iNOS gene has not been considered extensively. In this report, we explored the role of histone acetylation in interleukin (IL)-1β-mediated iNOS induction in cultured murine mesangial cells. Treatment of cells with the histone deacetylase inhibitor trichostatin A (TSA, 200 nM) resulted in a time-dependent, selective increase in histone H4 acetylation. TSA treatment of cells stably transfected with an iNOS promoter-luciferase construct inhibited IL-1β induction of endogenous nitric oxide and iNOS protein production and iNOS promoter-luciferase activity. Chromatin immunoprecipitation assays revealed that, under basal conditions, acetylated histone H4 associated with the region −978 to −710 of the iNOS promoter, a region rich in gene control elements and that IL-1β significantly increased this binding, which was further accentuated by cotreatment with TSA. Blockade of the phosphoinositide 3-kinase pathway with LY-294002 or the p70s6-kinase pathway with rapamycin in the presence of TSA and IL-1β inhibited 389Thr phosphorylation of p70s6 kinase, promoted binding of acetylated histone H4 to the iNOS promoter, and further suppressed iNOS protein expression and iNOS promoter activity. Thus TSA diminishes IL-1β-induced iNOS transcription through phosphoinositide 3-kinase- and p70s6 kinase-dependent pathways that increase site-specific histone H4 acetylation at the −978 to −710 region of the iNOS promoter. This novel epigenetic control mechanism extends the network of regulatory controls governing NO production in mesangial cells.

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