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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide location analysis of SMRT and NCoR in wild-type and Bcl6 knockout macrophages

ABSTRACT: Using ChIP-seq, we reveal the SMRT and NCoR co-repressor cistromes, which each consist of over 30,000 half-shared binding sites. Moreover, we identify Bcl6-bound sub-cistromes for each co-repressor, which are strongly concentrated on NF-κB-driven inflammatory and tissue remodeling genes. These results reveal a critical role for Bcl6 and its corepressors SMRT and NCoR in the prevention of atherosclerosis and chronic inflammation. Identification of SMRT and NCoR binding sites in wild-type and Bcl6 knockout primary bone-marrow derived macrophages

ORGANISM(S): Mus musculus

SUBMITTER: Ruth Yu

PROVIDER: E-GEOD-27033 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis.

Barish Grant D GD Yu Ruth T RT Karunasiri Malith S MS Becerra Diana D Kim Jason J Tseng Tiffany W TW Tai Li-Jung LJ Leblanc Matthias M Diehl Cody C Cerchietti Leandro L Miller Yury I YI Witztum Joseph L JL Melnick Ari M AM Dent Alexander L AL Tangirala Rajendra K RK Evans Ronald M RM

Cell metabolism 20120329 4

Chronic inflammation is a hallmark of atherosclerosis, but its transcriptional underpinnings are poorly understood. We show that the transcriptional repressor Bcl6 is an anti-inflammatory regulator whose loss in bone marrow of Ldlr(-/-) mice results in severe atherosclerosis and xanthomatous tendonitis, a virtually pathognomonic complication in patients with familial hypercholesterolemia. Disruption of the interaction between Bcl6 and SMRT or NCoR with a peptide inhibitor in vitro recapitulated ...[more]

PMID: 22465074

Similar Datasets

Genome-wide location analysis of SMRT and NCoR in wild-type and Bcl6 knockout macrophages

Project description:Using ChIP-seq, we reveal the SMRT and NCoR co-repressor cistromes, which each consist of over 30,000 half-shared binding sites. Moreover, we identify Bcl6-bound sub-cistromes for each co-repressor, which are strongly concentrated on NF-κB-driven inflammatory and tissue remodeling genes. These results reveal a critical role for Bcl6 and its corepressors SMRT and NCoR in the prevention of atherosclerosis and chronic inflammation.

2012-03-30 | GSE27033 | GEO

A Bcl6-Smrt/Ncor repression program controls atherosclerosis

Project description:This SuperSeries is composed of the following subset Series: GSE27001: Inhibition of Bcl6-SMRT/NCoR interactions by an inhibitory peptide affects inflammatory pathways GSE27033: Genome-wide location analysis of SMRT and NCoR in wild-type and Bcl6 knockout macrophages Refer to individual Series

2012-03-29 | E-GEOD-27060 | biostudies-arrayexpress

CDDP treatment of U2OS cells with NCOR and SMRT knock-down

Project description:We detected an interaction between checkpoint kinase Chk2 and some members of the NCOR/SMRT co-repressor complex. In order to study the role of gene repression in the checkpoint response to DNA damage, we performed RNA profiling in NCOR or SMRT knockdown cells after treztment with cisplatin. U2OS cells were transfected with siRNAs for NCOR or SMRT, grown for 2 days in complete medium, and then treated with 100 microM cisplatin (CDDP) for 6h. Biological duplicates were used for RNa profiling

2012-02-06 | E-GEOD-34226 | biostudies-arrayexpress

GEI-8, a homologue of vertebrate nuclear receptor corepressor NCoR/SMRT, regulates development and neuronal functions in C. elegans.

Project description:NCoR and SMRT are two paralogous vertebrate proteins that function as corepressors with unliganded nuclear receptors. Although C. elegans has a large number of nuclear receptors, orthologues of the corepressors NCoR and SMRT have not unambiguously been identified in Drosophila or C. elegans. Here, we identify GEI-8 as the closest homologue of NCoR and SMRT in C. elegans and demonstrate that GEI-8 is expressed as at least two isoforms throughout development in multiple tissues, including neurons, muscle and intestinal cells. We demonstrate that a homozygous deletion within the gei-8 coding region, which is predicted to encode a truncated protein lacking the predicted NR domain, results in severe mutant phenotypes with developmental defects, slow movement and growth, arrested gonadogenesis and defects in cholinergic neurotransmission. Whole genome expression analysis by microarrays identified sets of de-regulated genes consistent with both the observed mutant phenotypes and a role of GEI-8 in regulating transcription. Interestingly, the upregulated transcripts included a predicted mitochondrial sulfide:quinine reductase encoded by Y9C9A.16. This locus also contains non-coding, 21-U RNAs of the piRNA. Inhibition of the expression of the region coding for 21-U RNAs leads to irregular gonadogenesis in the homozygous gei-8 mutants, but not in an otherwise wild-type background, suggesting that GEI-8 may function in concert with the 21-U RNAs to regulate gonadogenesis. Our results confirm that GEI-8 is the orthologue of the vertebrate NCoR/SMRT corepressors and demonstrate important roles for this putative transcriptional corepressor in development and neuronal function. Comparison of Mutant vs. WT control with three replications per treatment group

2013-08-11 | E-GEOD-40127 | biostudies-arrayexpress

CDDP treatment of U2OS cells with NCOR and SMRT knock-down

2012-02-06 | GSE34226 | GEO

Gene expression profiling in NCoR deficient mouse livers

Project description:The thyroid hormone receptor (TR) has been proposed to regulate target genes in the absence of triiodothyronine (T3), through the recruitment of the corepressors, NCoR and SMRT. NCoR and SMRT may thus play a key role in both hypothyroidism and resistance to thyroid hormone, though this has never been tested in vivo. To accomplish this we developed mice that express in the liver a NCoR protein (L-NCoR∆ID) that cannot interact with the TR. L-NCoR∆ID mice develop normally, however when made hypothyroid the repression of many positively regulated T3-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by the unliganded TR. Remarkably, in the euthyroid state, expression of many T3-targets are also upregulated in L-NCoR∆ID mice, demonstrating that NCoR also determines the magnitude of the response to T3 in euthyroid animals. While positive T3 targets were upregulated in L-NCoR∆ID mice in the hypo and euthyroid state there was less effect seen on negatively regulated T3 target genes. Thus, NCoR is a specific regulator of T3-action in vivo and mediates the activity of the unliganded TR. Furthermore, NCoR may play a key role in determining the differences in individual responses to similar levels of circulating T3. Keywords: NCoR, thyroid hormone signaling, mouse liver, DNA Microarray To better assess the role of NCoR in positive and negative regulation we performed micorarray analysis of gene expression in the livers of euthyroid and hypothyroid control and L-NCoR∆ID mice.

2008-12-03 | E-GEOD-10001 | biostudies-arrayexpress

Inhibition of Bcl6-SMRT/NCoR interactions by an inhibitory peptide affects inflammatory pathways

Project description:Using microarrays, we compared the changes in levels of gene expression between wild type mouse bone marrow derived macrophages upon treatment with the Bcl6 peptide inhibitor, RI-BPI, that specifically blocks interaction between BCL6 and the co-repressors NCoR or SMRT.

2012-03-30 | GSE27001 | GEO

A biochemical basis for toggling enhancers from the active to poised state in B cells

Project description:BCL6 is crucial for B-cell activation and lymphomagenesis. We used integrative genomics to explore BCL6 mechanism in normal and malignant B-cells. Surprisingly, BCL6 assembled distinct complexes at enhancers vs. promoters. At enhancers BCL6 preferentially recruited SMRT, which mediated H3K27 deacetylation through HDAC3, antagonized p300 activity and repressed transcription, but without decommissioning enhancers. This provides a biochemical basis for toggling enhancers from the active to poised state. Virtually all SMRT was bound with BCL6 suggesting that in B-cells BCL6 uniquely sequesters SMRT from other factors. In promoters BCL6 preferentially recruited BCOR, but most potently repressed promoters where it formed a distinctive ternary complex with SMRT and BCOR. Promoter repression was associated with decreased H3K36me3, H3K79me2 and Pol II elongation, linking BCL6 to transcriptional pausing. We identified the binding patterns of BCL6, SMRT, NCOR and BCOR corepressors in normal germinal center B cells and a DLBCL cell line (OCI-Ly1) using ChIP-seq. Additionally we treated lymphoma cells with siRNA against BCL6 and a non-targeted siRNA (NT control) and performed RNA-seq to identify the genes bound and repressed by BCL6. RNA-seq experiments were performed at 24h and 48h after siRNA treatments. Additional biological triplicate RNA-seq experiments were performed at 48h after BCL6 knockdown. Furthermore, a series of histone mark ChIP-seq and RNA polymerase ChIP-seq (total, Ser5-P and Ser2-P) were preformed to capture the chromatin states associated with the formation of BCL6 corepressor complexes.

2013-08-05 | E-GEOD-29282 | biostudies-arrayexpress

Bcl6 and NFkB cistromes mediate opposing reulation of the innate immune response

Project description:Here, using ChIP-seq, we define the NF-κB cistrome which is comprised of 31,070 cis-acting binding sites responsive to LPS-induced signaling. In addition, we demonstrate that the transcriptional repressor B-cell lymphoma 6 (Bcl-6) regulates nearly a third of the Tlr4-regulated transcriptome and that 90% of the Bcl-6 cistrome is collapsed following Tlr4 activation. Bcl-6 deficient macrophages are acutely hypersensitive to lipopolysaccharide (LPS) and, using comparative ChIP-seq analyses, we find that the Bcl-6 and NF-κB cistromes intersect, within nucleosomal distance, at nearly half of Bcl-6 binding sites in stimulated macrophages to promote opposing epigenetic modifications of the local chromatin. These results reveal a genomic strategy for controlling the innate immune response in which repressive and inductive cistromes establish a dynamic balance between macrophage quiescence and activation via epigenetically marked cis-regulatory elements. keywords: Genome-wide location analysis Identification of BCL6 and NFkB binding sites in unstimulated and LPS-stimulated primary bone-marrow derived macrophages.

2010-11-24 | E-GEOD-16723 | biostudies-arrayexpress

Gene expression profiling in NCoR deficient mouse livers

2008-12-04 | GSE10001 | GEO

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