Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Brd4 regulation of activity dependent transcription

ABSTRACT: Inhibition of Brd4 with Jq1 in neurons with or without BDNF stimulation Examination of the effects of Jq1 treatment on primary mouse cortical neurons

ORGANISM(S): Mus musculus

SUBMITTER: Erica Korb

PROVIDER: E-GEOD-63809 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice.

Korb Erica E Herre Margo M Zucker-Scharff Ilana I Darnell Robert B RB Allis C David CD

Nature neuroscience 20150824 10

Precise regulation of transcription is crucial for the cellular mechanisms underlying memory formation. However, the link between neuronal stimulation and the proteins that directly interact with histone modifications to activate transcription in neurons remains unclear. Brd4 is a member of the bromodomain and extra-terminal domain (BET) protein family, which binds acetylated histones and is a critical regulator of transcription in many cell types, including transcription in response to external ...[more]

PMID: 26301327

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Project description:Selective bromodomains inhibitors block the interaction between diverse bromodomains and extraterminal domains (BET) proteins and acetylated proteins. These inhibitors have shown beneficial effects in cancers malignancies and experimental inflammation in mouse models, but data on renal diseases are scarce. We have investigated the effect of the BET proteins inhibitor JQ1 in a mice model of unilateral ureteral obstruction. Treatment with JQ1 diminished renal damage, the presence of inflammatory cell infiltration and the upregulation of proinflammatory genes. The in vitro evaluation of JQ1 on TNF-Î± inducible genes in renal cells showed that BET inhibition modulated several biological processes, including inflammation or immune response. Moreover, gene-silencing experiments showed that BRD4 regulates several proinflammatory genes (IL-6, CCL-2 and CCL-5) and chromatin immunoprecipitation techniques demonstrated that BRD4 specifically binds to acetylated histone H3 in the promoter region of those genes. The nuclear factor-ï«B (NF-ï«B) pathway regulates renal inflammation. The RelA NF-ï«B subunit is activated by acetylation of lysine 310. In damaged kidneys and in TNF-Î±-treated renal cells, JQ1 blocked the nuclear translocation of RelA/NF-ï«B and NF-ï«B-mediated gene expression. Additionally, obstructed kidneys showed an activation of the Th17 immune response, which was diminished by JQ1 treatment. Our results demonstrate that the BET inhibition decreases renal inflammation by 3 independent mechanisms: 1) chromatin remodelling in the promoter regions of specific genes, 2) blocking NF-ï«B pathway activation, and 3) modulating the Th17 immune response. These results suggest that BET inhibitors could have important therapeutic applications in inflammatory renal diseases. HK2 cell line was treated with JQ1 or its enantiomer JQ1(-) (500nM) for 1 hour before stimulation or not with TNF-Î± (5ng/ml) for additional 3h. We analized the genes up- and down-regulated by TNF-Î± vs unstimulated cells, and further the genes downregulated or unaffected by JQ1 compared to the cells treated with the enantiomer (-) JQ1.

Project description:Epigenetic pathways regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. While chromatin alterations are, in principle, reversible and often amendable to drug intervention, the promise of targeting such pathways therapeutically has been hampered by our limited understanding of cancer-specific epigenetic dependencies. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukemia (AML) – an aggressive hematopoietic malignancy often associated with aberrant chromatin states. By screening a custom shRNA library targeting known chromatin regulators in a genetically defined AML mouse model, we identify the bromodomain-containing protein Brd4 as a critical requirement for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust anti-leukemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation. Extensive evaluation of JQ1-sensitivity in primary human leukemia samples and in established cell lines revealed a broad activity of this compound against diverse AML subtypes. These effects are, at least in part, due to a requirement for Brd4 in maintaining Myc expression and promoting aberrant self-renewal. Together, our results indicate that Brd4 is a promising therapeutic target in AML and identify a small molecule that efficiently targets Myc. These findings also highlight the utility of RNAi screening as a discovery platform for revealing epigenetic vulnerabilities for direct pharmacologic intervention in cancer. In order to understand downstream targets of Brd4, we performed array in murine or human MLL-AF9/NrasG12D cell line under the condition that Brd4 was suppressed by using shRNAs or the small molecule inhibitor JQ1. To test the hypothesis that Myc might be an important target of Brd4, we performed arrary on murine ectopic Myc overexpression MLL-AF9/NrasG12D cell under JQ1 treatment.

Dataset Information

Brd4 regulation of activity dependent transcription

Publications

BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice.

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