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Genome-wide landscape of liver X receptor chromatin binding and gene regulation

ABSTRACT: Gene expression: Identification of primary target genes of liver X receptor (LXR) in an immune-related cellular model (THP-1 cells) to study, in conjunction with LXR binding data from ChIP-seq, the genome-wide mechanisms of transcriptional regulation by LXR. ChIP-Seq: We performed ChIP-seq in macrophage-type PMA-differentiated THP-1 cells after stimulation with the potent synthetic LXR ligand T0901317 (T09). As a reference we performed microarray gene expression analysis in the same cellular model. We identified in total 1357 LXR binding locations on chromatin (FDR < 1%), of which 526 were observed after T09 treatment. De novo analysis of LXR site sequences identified DR4-type binding sites as major motif.

ORGANISM(S): Homo sapiens

PROVIDER: GSE28319 | GEO | 2012/02/02

SECONDARY ACCESSION(S): PRJNA139339

REPOSITORIES: GEO

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Genome-wide landscape of liver X receptor chromatin binding and gene regulation

Project description:Gene expression: Identification of primary target genes of liver X receptor (LXR) in an immune-related cellular model (THP-1 cells) to study, in conjunction with LXR binding data from ChIP-seq, the genome-wide mechanisms of transcriptional regulation by LXR. ChIP-Seq: We performed ChIP-seq in macrophage-type PMA-differentiated THP-1 cells after stimulation with the potent synthetic LXR ligand T0901317 (T09). As a reference we performed microarray gene expression analysis in the same cellular model. We identified in total 1357 LXR binding locations on chromatin (FDR < 1%), of which 526 were observed after T09 treatment. De novo analysis of LXR site sequences identified DR4-type binding sites as major motif. gene expression: THP-1 cells were treated for 4 h with 1 M-BM-5M T09 or vehicle (DMSO) ChIP-Seq: PMA-differentiated THP-1 cells were treated for 60 min with 1 M-BM-5M T09 or vehicle (DMSO)

2012-02-02 | E-GEOD-28319 | biostudies-arrayexpress

Genome-wide profiling of LXR, RXR and PPARM-NM-1 in mouse liver reveals extensive sharing of binding sites

Project description:The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice is dependent on LXR and correlates with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the role of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as PPAR signaling pathways, and subsequent ChIP-seq mapping of PPARM-NM-1 binding demonstrated binding of PPARM-NM-1 to 71-88% of the identified LXR:RXR binding sites. Sequence analysis of shared binding regions combined with sequential ChIP on selected sites indicate that LXR:RXR and PPARM-NM-1:RXR bind to degenerate response elements in a mutually exclusive manner. Together our findings suggest extensive and unexpected cross-talk between hepatic LXR and PPARM-NM-1 at the level of binding to shared genomic sites LXR, RXR, PPARalpha and RNA Polymerase II ChIP-seq on livers from female C57BL/6 wild-type and/or LXRM-NM-1/M-NM-2-deficient mice (13 weeks of age, n=1) treated by oral gavage once daily for 14 days with the RXR agonist bexarotene (100 mg/kg body weight [mpk], in 1% carboxymethylcellulose), the LXR agonist T0901317 (T09, 30 mpk) or vehicle alone.

2012-01-31 | E-GEOD-35262 | biostudies-arrayexpress

Genome-wide profiling of LXR, RXR and PPARα in mouse liver reveals extensive sharing of binding sites

Project description:The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice is dependent on LXR and correlates with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the role of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as PPAR signaling pathways, and subsequent ChIP-seq mapping of PPARα binding demonstrated binding of PPARα to 71-88% of the identified LXR:RXR binding sites. Sequence analysis of shared binding regions combined with sequential ChIP on selected sites indicate that LXR:RXR and PPARα:RXR bind to degenerate response elements in a mutually exclusive manner. Together our findings suggest extensive and unexpected cross-talk between hepatic LXR and PPARα at the level of binding to shared genomic sites

2012-01-31 | GSE35262 | GEO

Liver X receptor beta is the dominant LXR subtype in skeletal muscle

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2010-03-30 | E-GEOD-13192 | biostudies-arrayexpress

VDR ChIP-seq in PMA-differentiated macrophages (human M2-type like macrophages)

Project description:We performed ChIP-seq in macrophage-type PMA-differentiated THP-1 cells after stimulation with the the natural VDR ligand 1,25dihydroxyvitamin D3 (1,25D). We identified in total 223 VDR binding locations on chromatin after 1,25D treatment. De novo analysis of VDR site sequences identified DR3-type binding sites as major motif.

2016-07-13 | GSE51181 | GEO

Transcription profiling of mouse LXRalpha null, LXRbeta null mutants reveals liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRalpha (NR1H3) and LXRbeta (NR1H2) subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRalpha and LXRbeta knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRalpha KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRbeta KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRalpha KO mice, but not LXRbeta KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRbeta in skeletal muscle.

2009-10-01 | E-MTAB-61 | biostudies-arrayexpress

Effect of T0901317, AM580 or T0901317+AM580 on monocyte gene expression

Project description:The aim of this study was to investigate the effect of T0901317 LXR agonist on Retinoic Acid Receptor (RAR) family gene expression. T0901317 alone increase RARalpha gene expression in monocytes and the effects of the co treatment of the cells with T0901317 and a specific RARalpha agonist (AM580) were further studied. For this monocytes were treated for 24h with DMSO or T0901317 to induce RARalpha expression and in a second step cells were treated or not with AM580 for another 24h period. Gene expression was analysed for all the treatments (T0901317, AM580 or T0901317+AM580) and we focussed on genes which expression was synergitically induced by the co treatment as compared to the cells treated either by T0901317 or AM580. Monocytes were obtained from 2 healthy donors with inform consent. Cells were treated in vitro with the vehicle (DMSO 0,1%) or 10ÂµM of the LXR agonist T0901317 for 24 hours. Then after cells were treated for another 24 hour period with or without 100nM of the RARalpha specific agonist AM580.

2010-04-08 | E-GEOD-13407 | biostudies-arrayexpress

Liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRα and LXRβ subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRα and LXRβ knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRα KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRβ KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRα KO mice, but not LXRβ KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRβ in skeletal muscle.

2010-03-31 | GSE13192 | GEO

Impact of LXR activation on alternatively activated human macrophages

Project description:To investigate how LXR activation potentiates expression of Th2 cytokine-dependent genes in primary human macrophages, we pulsed macrophages with synthetic LXR ligand T0901317 then polarized cells to alternatively activated macrophages with IL-4 or IL-13.

2021-04-14 | GSE158022 | GEO

Transcription profiling of livers from Low Density Lipoprotein Receptor null mice expressing human LXR alpha to explore the molecular basis of metabolic effects of increased hepatic hLXR alpha.

Project description:Microarray analysis of liver RNA from male Low Density Lipoprotein Receptor null mice on C57B6 background expressing human LXR alpha or GFP (control) via adeno-associated virus (AAV2.8) gene transfer, under control of the liver specific human thyroxine binding globulin promoter. Samples are from 8 month old mice, with AAV treatment at age of 10 weeks, on Western diet for 12 weeks prior experiment. The synthetic LXR ligand T0901317 (5mg/kg) or vehicle was administered for 3 days by i.p. injection to designated mice.

2007-08-31 | E-GEOD-2644 | biostudies-arrayexpress

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