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Orphan nuclear receptor TR4 uses non-equivalent binding sites to regulate gene targets from proximal and distal transcriptional regulatory elements during human definitive erythropoiesis [ChIP-seq]

ABSTRACT: In this study, we resolved the genome-wide binding of TR4 in differentiating human erythroid cells by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq). We found that TR4 preferentially binds to DR1 elements in the promoters of its target genes, and that the majority of these genes encode proteins that participate in fundamental biological functions such as mRNA processing, translation, RNA splicing and primary metabolic process. Interestingly, we also found an increased occurrence of other repeat element motifs (such as DR4, IR1 and ER6) at TR4-bound distal sites that are located more than 10 Kbp away from the nearest gene. This raises the tantalizing possibility that TR4 may heterodimerize with unique partners, including other nuclear receptors such as RXR, thus allowing TR4 to elicit unique transcriptional responses when acting at proximal (promoter) and distal (enhancer and silencer) regulatory sites during human erythropoiesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54759 | GEO | 2015/02/04

SECONDARY ACCESSION(S): PRJNA237564

REPOSITORIES: GEO

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Project description:Background: The orphan nuclear receptor TR4 (human testicular receptor 4 or NR2C2) plays a pivotal role in a variety of biological and metabolic processes. With no known ligand and few known target genes, the mode of TR4 function was unclear. Results: We report the first genome-wide identification and characterization of TR4 in vivo binding. Using chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq), we identified TR4 binding sites in 4 different human cell types and found that the majority of target genes were shared among different cells. TR4 target genes are involved in fundamental biological processes such as RNA metabolism and protein translation. In addition, we found that a subset of TR4 target genes exerts cell-type specific functions. Analysis of the TR4 binding sites revealed that less than 30% of the peaks from any of the cell types contained the DR1 motif previously derived from in vitro studies, suggesting that TR4 may be recruited to the genome via interaction with other proteins. A bioinformatics analysis of the TR4 binding sites predicted a cis regulatory module involving TR4 and ETS transcription factors. To test this prediction, we performed ChIP-seq for the ETS factor ELK4 and found that 30% of TR4 binding sites were also bound by ELK4. Motif analysis of the sites bound by both factors revealed a lack of the DR1 element, suggesting that TR4 binding at a subset of sites is facilitated through the ETS transcription factor ELK4. Further studies will be required to investigate the functional interdependence of these two factors. Conclusions: Our data suggest that TR4 plays a pivotal role in fundamental biological processes across different cell types. In addition, the identification of cell type specific TR4 binding sites enables future studies of the pathways underlying TR4 action and its possible role in metabolic diseases. This is one part of the study that involved the examination of HepG2 gene expression. Biological triplicate Illumina Sentrex bead arrays.

Project description:The orphan nuclear receptor TR4 (human testicular receptor 4 or NR2C2) plays a pivotal role in a variety of biological and metabolic processes. With no known ligand and few known target genes, the mode of TR4 function was unclear. We report the first genome-wide identification and characterization of TR4 in vivo binding. Using chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq), we identified TR4 binding sites in 4 different human cell types and found that the majority of target genes were shared among different cells. TR4 target genes are involved in fundamental biological processes such as RNA metabolism and protein translation. In addition, we found that a subset of TR4 target genes exerts cell-type specific functions. Analysis of the TR4 binding sites revealed that less than 30% of the peaks from any of the cell types contained the DR1 motif previously derived from in vitro studies, suggesting that TR4 may be recruited to the genome via interaction with other proteins. A bioinformatics analysis of the TR4 binding sites predicted a cis regulatory module involving TR4 and ETS transcription factors. To test this prediction, we performed ChIP-seq for the ETS factor ELK4 and found that 30% of TR4 binding sites were also bound by ELK4. Motif analysis of the sites bound by both factors revealed a lack of the DR1 element, suggesting that TR4 binding at a subset of sites is facilitated through the ETS transcription factor ELK4. Further studies will be required to investigate the functional interdependence of these two factors. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf 8 total ChIP-seq datasets; four TR4 and datasets done in duplicate from 4 different cell lines; ELK4 (Sap1a) duplicate dataset done from HeLa cells; 1 ELK1 replicate in HeLa cells, 2 individual replicates for histone mod datasets from K562 cells

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Orphan nuclear receptor TR4 uses non-equivalent binding sites to regulate gene targets from proximal and distal transcriptional regulatory elements during human definitive erythropoiesis [ChIP-seq]

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