Role of Nuclear Receptor Coactivator 3 (Ncoa3) in Pluripotency Maintenance

Wu, Zhaoting; Yang, Meng; Liu, Hongjie; Guo, Hongchao; Wang, Yuan; Cheng, Hong; Chen, Lingyi

doi:10.1074/jbc.m112.373092

Cited by 46 publications

(43 citation statements)

References 52 publications

(24 reference statements)

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“…Moreover, Ncoa3 reportedly binds to the Nanog promoter and enhances its activity via its effects on the histone modification enzymes CBP and CARM1 [36]. Ncoa3 was also associated with Esrrb and activated several genes involved in self-renewal and pluripotency [28].…”

Section: Discussionmentioning

confidence: 99%

“…Ncoa3 is expressed in ES cells, and functional inhibition by shRNA led to morphological changes, reduced expression of the pluripotency genes Nanog, Oct3/4, and Sox2, and impaired differentiation potential [36]. Moreover, Ncoa3 reportedly binds to the Nanog promoter and enhances its activity via its effects on the histone modification enzymes CBP and CARM1 [36].…”

Section: Discussionmentioning

confidence: 99%

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Esrrb directly binds to Gata6 promoter and regulates its expression with Dax1 and Ncoa3

Uranishi

Akagi

Koide

et al. 2016

Biochemical and Biophysical Research Communications

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Estrogen-related receptor beta (Esrrb) is expressed in embryonic stem (ES) cells and is involved in self-renewal ability and pluripotency. Previously, we found that Dax1 is associated with Esrrb and represses its transcriptional activity. Further, the disruption of the Dax1-Esrrb interaction increases the expression of the extra-embryonic endoderm marker Gata6 in ES cells. Here, we investigated the influences of Esrrb and Dax1 on Gata6 expression. Esrrb overexpression in ES cells induced endogenous Gata6 mRNA and Gata6 promoter activity. In addition, the Gata6 promoter was found to contain the Esrrb recognition motifs ERRE1 and ERRE2, and the latter was the responsive element of Esrrb. Associations between ERRE2 and Esrrb were then confirmed by biotin DNA pulldown and chromatin immunoprecipitation assays. Subsequently, we showed that Esrrb activity at the Gata6 promoter was repressed by Dax1, and although Dax1 did not bind to ERRE2, it was associated with Esrrb, which directly binds to ERRE2. In addition, the transcriptional activity of Esrrb was enhanced by nuclear receptor co-activator 3 (Ncoa3), which has recently been shown to be a binding partner of Esrrb.Finally, we showed that Dax1 was associated with Ncoa3 and repressed its transcriptional activity. Taken together, the present study indicates that the Gata6 pCAGIP-Myc-Dax1, and pCAGIP-Myc-Dax1LTm, were generated as described previously [9,21]. The Ncoa3 coding region and its truncated mutants were amplified using polymerase chain reaction (PCR) before being cloned into expression vectors.The Gata6 gene promoter region (-0.9 kb) was amplified using PCR and was cloned into pGL4.10 (Promega, Madison, WI, USA) to produce the plasmid pGL4.10-Gata6P 0.9k. To construct the Esrrb-responsive element (ERRE)-mutant pGL4.10-Gata6P 0.9k plasmids, mutant ERRE1 or ERRE2 elements were generated using PCR with specific primers. PCR products were then cloned into pGL4.10 to produce pGL4.10-Gata6P 0.9k-ERRE1 mut and -ERRE2 mut vectors. All primer sequences are listed in Supplemental Table S1. 9Plasmids were introduced into cultured cells using Lipofectamine 2000 (Life Technologies, Grand Island, NY, USA). Two days after transfection, cells were treated with 1 μg/mL puromycin for 5-7 days, and RNA samples for RT-PCR were isolated and examined as described previously [21]. The cell extracts for the luciferase assays were prepared 48 h after transfection, and luciferase activity was measured using a luciferase assay kit (Promega) and an AB-2200 luminometer (ATTO, Tokyo, Japan). Biotin-labeled DNA pull-down and chromatin immunoprecipitation assaysBiotin-labeled DNA pull-down assays were performed as described previously [21]. Briefly, biotin-labeled oligonucleotides were incubated with A3-1 ES extracts or HEK293 cell extracts that had been transfected with pCAGIP-Myc-Dax1 and/or pCAGIP-Esrrb in the presence of streptavidin-agarose (Novagen, Darmstadt, Germany).Subsequently, non-labeled oligonucleotide (either wild-type or mutant) was added for competition assays at a ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Esrrb directly binds to Gata6 promoter and regulates its expression with Dax1 and Ncoa3

Uranishi

Akagi

Koide

et al. 2016

Biochemical and Biophysical Research Communications

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“…In addition to the involvement of SRCs in cancer (70), recent evidence points to a requirement for coactivators in chemoresistance (71) as well as in stem cell self-renewal and pluripotency maintenance (72, 73). Under cytotoxic stress, SRC-3 deregulates p53 induction by upregulating TNF receptor–associated factor 4 (TRAF4), which competes with p53 for binding to the deubiquitinase HAUSP (herpesvirus-associated ubiquitin-specific protease).…”

Section: The Role Of Nuclear Receptor Coactivators In Human Disease Amentioning

confidence: 99%

Nuclear Receptor Coactivators: Master Regulators of Human Health and Disease

2014

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Transcriptional coregulators (coactivators and corepressors) have emerged as the principal modulators of the functions of nuclear receptors and other transcription factors. During the decade since the discovery of steroid receptor coactivator-1 (SRC-1), the first authentic coregulator, more than 400 coregulators have been identified and characterized, and deciphering their function has contributed significantly to our understanding of their role in human physiology. Deregulated expression of coregulators has been implicated in diverse disease states and related pathologies. The advancement of molecular technologies has enabled us to better characterize the molecular associations of the SRC family of coactivators with other protein complexes in the context of gene regulation. These continuing discoveries not only expand our knowledge of the roles of coactivators in various human diseases but allow us to discover novel coactivator-targeting strategies for therapeutic intervention in these diseases.

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“…While this manuscript was under revision, two overlapping studies were published demonstrating that SRC3/NCoA3 contributes to pluripotency maintenance in mESCs. p/CIP/SRC3 is required for the expression of several critical pluripotency genes including Nanog, KlF4, Dax1, and Tbx1 [52,53] and is essential for controlling Esrrb-dependant activation suggesting that SRC3/NCoA3 is a key member of the pluripotency transcriptional circuitry.…”

Section: Discussionmentioning

confidence: 99%

Critical Components of the Pluripotency Network Are Targets for the p300/CBP Interacting Protein (p/CIP) in Embryonic Stem Cells

Chitilian

Thillainadesan

Manias³

et al. 2014

Stem Cells

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p/CIP, also known as steroid receptor coactivator 3 (SRC-3)/Nuclear Receptor Coactivator 3 (NCoA3), is a transcriptional coactivator that binds liganded nuclear hormone receptors, as well as other transcription factors, and facilitates transcription through direct recruitment of accessory factors. We have found that p/CIP is highly expressed in undifferentiated mouse embryonic stem cells (mESCs) and is downregulated during differentiation. siRNA-mediated knockdown of p/CIP decreased transcript levels of Nanog, but not Oct4 or Sox2. Microarray expression analysis showed that Klf4, Tbx3, and Dax-1 are significantly downregulated in mESCs when p/CIP is knocked down. Subsequent chromatin immunoprecipitation (ChIP) analysis demonstrated that Tbx3, Klf4, and Dax-1 are direct transcriptional targets of p/CIP. Using the piggyBac transposition system, a mouse ESC line that expresses Flag-p/CIP in a doxycycline-dependent manner was generated. p/CIP overexpression increased the level of target genes and promoted the formation of undifferentiated colonies. Collectively, these results indicate that p/CIP contributes to the maintenance of ESC pluripotency through direct regulation of essential pluripotency genes.

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Role of Nuclear Receptor Coactivator 3 (Ncoa3) in Pluripotency Maintenance

Cited by 46 publications

References 52 publications

Esrrb directly binds to Gata6 promoter and regulates its expression with Dax1 and Ncoa3

Esrrb directly binds to Gata6 promoter and regulates its expression with Dax1 and Ncoa3

Nuclear Receptor Coactivators: Master Regulators of Human Health and Disease

Critical Components of the Pluripotency Network Are Targets for the p300/CBP Interacting Protein (p/CIP) in Embryonic Stem Cells

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