Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes

Henriette O'Geen, Yu Hsuan Lin, Xiaoqin Xu, Lorigail Echipare, Vitalina M. Komashko, Daniel He, Seth Frietze, Osamu Tanabe, Lihong Shi, Maureen A. Sartor, James D. Engel, Peggy J. Farnham

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Abstract

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.

Original languageEnglish (US)
Article number689
JournalBMC Genomics
Volume11
Issue number1
DOIs
StatePublished - Dec 2 2010

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Nuclear Receptor Subfamily 2, Group C, Member 2
Biological Phenomena
Genome
Binding Sites
Genes
Transcription Factors
Chromatin Immunoprecipitation
Metabolic Diseases
Protein Biosynthesis
Computational Biology
RNA
Ligands

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

O'Geen, H., Lin, Y. H., Xu, X., Echipare, L., Komashko, V. M., He, D., ... Farnham, P. J. (2010). Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes. BMC Genomics, 11(1), [689]. https://doi.org/10.1186/1471-2164-11-689

Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes. / O'Geen, Henriette; Lin, Yu Hsuan; Xu, Xiaoqin; Echipare, Lorigail; Komashko, Vitalina M.; He, Daniel; Frietze, Seth; Tanabe, Osamu; Shi, Lihong; Sartor, Maureen A.; Engel, James D.; Farnham, Peggy J.

In: BMC Genomics, Vol. 11, No. 1, 689, 02.12.2010.

Research output: Contribution to journalArticle

O'Geen, H, Lin, YH, Xu, X, Echipare, L, Komashko, VM, He, D, Frietze, S, Tanabe, O, Shi, L, Sartor, MA, Engel, JD & Farnham, PJ 2010, 'Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes', BMC Genomics, vol. 11, no. 1, 689. https://doi.org/10.1186/1471-2164-11-689
O'Geen, Henriette ; Lin, Yu Hsuan ; Xu, Xiaoqin ; Echipare, Lorigail ; Komashko, Vitalina M. ; He, Daniel ; Frietze, Seth ; Tanabe, Osamu ; Shi, Lihong ; Sartor, Maureen A. ; Engel, James D. ; Farnham, Peggy J. / Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes. In: BMC Genomics. 2010 ; Vol. 11, No. 1.
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abstract = "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.",
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AU - Komashko, Vitalina M.

AU - He, Daniel

AU - Frietze, Seth

AU - Tanabe, Osamu

AU - Shi, Lihong

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AU - Engel, James D.

AU - Farnham, Peggy J.

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AB - 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.

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