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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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54761 | GEO | 2015/02/04

SECONDARY ACCESSION(S): PRJNA237563

REPOSITORIES: GEO

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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

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-02-04 | E-GEOD-54761 | biostudies-arrayexpress

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

Project description:We knocked down TR4 expression by 2 lentiviral mediated vectors at day 11 of erythroid differentiation in order to identify TR4 downstream targets. Two lentiviruses and one empty control were used to knockdown TR4 expression. The cells were harvested at day 11 during erythroid differentiation.

2015-02-04 | E-GEOD-54760 | biostudies-arrayexpress

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]

Project description: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. Examination of TR4 genome wild binding in human erythroid cells, which are harvested at day 8, 11 and 14 during in vitro differentiation. Two replicates were included for each differentiation stage.

2015-02-04 | E-GEOD-54759 | biostudies-arrayexpress

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

Project description:We knocked down TR4 expression by 2 lentiviral mediated vectors at day 11 of erythroid differentiation in order to identify TR4 downstream targets.

2015-02-04 | GSE54760 | GEO

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]

2015-02-04 | GSE54759 | GEO

Biased, non-equivalent gene-proximal and -distal binding motifs of orphan nuclear receptor TR4 in primary human erythroid cells.

Project description:We previously reported that TR2 and TR4 orphan nuclear receptors bind to direct repeat (DR) elements in the ?- and ?-globin promoters, and act as molecular anchors for the recruitment of epigenetic corepressors of the multifaceted DRED complex, thereby leading to ?- and ?-globin transcriptional repression during definitive erythropoiesis. Other than the ?- and ?-globin and the GATA1 genes, TR4-regulated target genes in human erythroid cells remain unknown. Here, we identified TR4 binding sites genome-wide using chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) as human primary CD34(+) hematopoietic progenitors differentiated progressively to late erythroid precursors. We also performed whole transcriptome analyses by RNA-seq to identify TR4 downstream targets after lentiviral-mediated TR4 shRNA knockdown in erythroid cells. Analyses from combined ChIP-seq and RNA-seq datasets indicate that DR1 motifs are more prevalent in the proximal promoters of TR4 direct target genes, which are involved in basic biological functions (e.g., mRNA processing, ribosomal assembly, RNA splicing and primary metabolic processes). In contrast, other non-DR1 repeat motifs (DR4, ER6 and IR1) are more prevalent at gene-distal TR4 binding sites. Of these, approximately 50% are also marked with epigenetic chromatin signatures (such as P300, H3K27ac, H3K4me1 and H3K27me3) associated with enhancer function. Thus, we hypothesize that TR4 regulates gene transcription via gene-proximal DR1 sites as TR4/TR2 heterodimers, while it can associate with novel nuclear receptor partners (such as RXR) to bind to distant non-DR1 consensus sites. In summary, this study reveals that the TR4 regulatory network is far more complex than previously appreciated and that TR4 regulates basic, essential biological processes during the terminal differentiation of human erythroid cells.

| S-EPMC4014424 | biostudies-literature

The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation.

Project description:The orphan nuclear receptors TR4 (NR2C2) and TR2 (NR2C1) are the DNA-binding subunits of the macromolecular complex, direct repeat erythroid-definitive, which has been shown to repress ?- and ?-globin transcription during adult definitive erythropoiesis. Previous studies implied that TR2 and TR4 act largely in a redundant manner during erythroid differentiation; however, during the course of routine genetic studies, we observed multiple variably penetrant phenotypes in the Tr4 mutants, suggesting that indirect effects of the mutation might be masked by multiple modifying genes. To test this hypothesis, Tr4+/- mutant mice were bred into a congenic C57BL/6 background and their phenotypes were reexamined. Surprisingly, we found that homozygous Tr4 null mutant mice expired early during embryogenesis, around embryonic day 7.0, and well before erythropoiesis commences. We further found that Tr4+/- erythroid cells failed to fully differentiate and exhibited diminished proliferative capacity. Analysis of Tr4+/- mutant erythroid cells revealed that reduced TR4 abundance resulted in decreased expression of genes required for heme biosynthesis and erythroid differentiation (Alad and Alas2), but led to significantly increased expression of the proliferation inhibitory factor, cyclin dependent kinase inhibitor (Cdkn1c) These studies support a vital role for TR4 in promoting erythroid maturation and proliferation, and demonstrate that TR4 and TR2 execute distinct, individual functions during embryogenesis and erythroid differentiation.

| S-EPMC5721283 | biostudies-literature

TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4.

Project description:The nuclear orphan receptor TAK1/TR4 functions as a positive as well as a negative regulator of transcription; however, little is known about the factors regulating or mediating its activity. Yeast two-hybrid analysis using the ligand-binding domain (LBD) of TAK1 as bait identified a novel TAK1-interacting protein, referred to as TIP27, which functions as a repressor of TAK1-mediated transactivation. TIP27 is a 27 kDa protein containing two zinc finger motifs. Mammalian two-hybrid analysis showed that TIP27 interacts specifically with TAK1 and not with several other nuclear receptors tested. The region between Asp39 and Lys79 of TIP27, referred to as TAK1-interaction domain (TID), is critical for its interaction with TAK1 while the TAK1-LBD from helix 3 until the C-terminus is required for the optimal interaction with TIP27. Pull-down assays demonstrated that the TIP27 physically interacts with TAK1 and supported the critical importance of the TID. Confocal microscopy showed that in the nucleus, TIP27 and TAK1 co-localize. TIP27 acts as a strong repressor of DR1-dependent transcriptional activation by TAK1. This repression does not involve the inhibition of TAK1 homodimerization or DR1 binding but may be due to an effect on co-activator recruitment by TAK1. Our results indicate that TIP27 functions as a TAK1-selective repressor.

| S-EPMC514368 | biostudies-literature

The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor.

Project description:Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.

| S-EPMC3024783 | biostudies-literature

Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.

Project description:Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.

| S-EPMC3666748 | biostudies-literature

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