Emerging roles of the corepressors NCoR1 and SMRT in homeostasis

Mottis, Adrienne; Mouchiroud, Laurent; Auwerx, Johan

doi:10.1101/gad.214023.113

Cited by 264 publications

(307 citation statements)

References 122 publications

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“…PRDM16, which is involved in differentiation of brown adipose tissue [31] and stem cell maintenance [32], was hypermethylated on six CpG sites. NCOR2, a co-repressor of importance for homeostatic processes, inflammation and circadian rhythms [33], had five hypermethylated CpGs and one hypomethylated CpG. We then assessed the presence of regions of vulnerability to methylation across the whole genome.…”

Section: Resultsmentioning

confidence: 99%

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

et al. 2016

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Aims/hypothesis Intrauterine growth restriction (IUGR) is associated with increased susceptibility to obesity, metabolic syndrome and type 2 diabetes. Although the mechanisms underlying the developmental origins of metabolic disease are poorly understood, evidence suggests that epigenomic alterations play a critical role. We sought to identify changes in DNA methylation patterns that are associated with IUGR in CD3 + T cells purified from umbilical cord blood obtained from male newborns who were appropriate for gestational age (AGA) or who had been exposed to IUGR. Methods CD3 + T cells were isolated from cord blood obtained from IUGR and AGA infants. The genome-wide methylation profile in eight AGA and seven IUGR samples was determined using the HELP tagging assay. Validation analysis using targeted bisulfite sequencing and bisulfite massARRAY was performed on the original cohort as well as biological replicates consisting of two AGA and four IUGR infants. The Segway algorithm was used to identify methylation changes within regulatory regions of the genome. Results A global shift towards hypermethylation in IUGR was seen compared with AGA (89.8% of 4,425 differentially methylated loci), targeted to regulatory regions of the genome, specifically promoters and enhancers. Pathway analysis identified dysregulation of pathways involved in metabolic disease (type 2 diabetes mellitus, insulin signalling, mitogen-activated protein kinase signalling) and T cell development, regulation and activation (T cell receptor signalling), as well as transcription factors (TCF3, LEF1 and NFATC) that regulate T cells. Furthermore, bump-hunting analysis revealed differentially methylated regions in PRDM16 and HLA-DPB1, genes important for adipose tissue differentiation, stem cell maintenance and function and T cell activation. Conclusions/interpretation Our findings suggest that the alterations in methylation patterns observed in IUGR CD3 + T cells may have functional consequences in targeted genes, regulatory regions and transcription factors. These may serve as biomarkers to identify those at 'high risk' for diminished attainment of full health potential who can benefit from early interventions.

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Section: Resultsmentioning

confidence: 99%

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

et al. 2016

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“…We also have shown that, in contrast with the native receptor, TRβ mutants unable to bind the corepressor cannot antagonize Ras-mediated transformation and tumorigenesis (26), reinforcing the idea that NCoR is an essential mediator of the tumor-suppressive actions of TRβ. TRβ-mediated up-regulation of NCoR could extend the scope of genes that are influenced by the receptor, because the corepressor has been shown to repress transcription through other nuclear receptors and numerous transcription factors with a role in cancer progression (1,12). Therefore, repression of prometastatic gene expression could be a consequence of NCoR interaction with this receptor or, more likely, with other transcription factors that associate with their promoters.…”

Section: Discussionmentioning

confidence: 99%

“…As expected from their prevalent role in integrating the action of many transcription factors, NCoR and HDAC3 affect numerous developmental and homeostatic processes (12). In addition, there is increasing evidence that NCoR could play a significant role in cancer.…”

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confidence: 99%

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

Martínez-Iglesias

Alonso-Merino

Gómez-Rey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.nuclear corepressor 1 | thyroid hormone receptor | tumor growth | metastasis | transcription

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“…In the absence of ligand, some NRs, such as the thyroid hormone receptor (THR) and retinoic acid receptor, repress gene expression by interacting with transcription corepressors including nuclear receptor corepressor 1 (NCoR1) and silencing mediator of retinoid and thyroid receptors (SMRT) (24); binding of NR antagonists can also lead to corepressor recruitment (25). Both NCoR1 and SMRT are large (Ͼ250 kDa) pro-teins that bind histone deacetylase complexes and contain multiple NR interaction domains at their C termini (26). Interaction domain motifs are composed of short amphipathic helices with an I/LXXI/VIXXXL/F/Y consensus that associate with NRs by binding to a hydrophobic cleft on the LBD (27).…”

mentioning

confidence: 99%

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Carter

Gupta

Ragsdale

2016

Journal of Biological Chemistry

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Rev-erb␣ and Rev-erb␤ are heme-binding nuclear receptors (NR) that repress the transcription of genes involved in regulating metabolism, inflammation, and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erb␣ recruits nuclear receptor corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases the affinity of the ligand-binding domain of Rev-erb NRs for NCoR1 peptides. One explanation for this discrepancy is that the ligand-binding domain and NCoR1 peptides used for in vitro studies cannot replicate the key features of the full-length proteins used in cellular studies. However, the combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erb␤ (FLRev-erb␤) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo-and heme-replete FLRev-erb␤⅐DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erb␤⅐NCoR1 complex. The interaction between FLRev-erb␤ and NCoR1 as well as Reverb␤ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating the degradation of Rev-erb␤ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10 ؊6 s ؊1 ) of heme dissociation from Rev-erb␤ rules out a prior proposal that Reverb␤ acts as an intracellular heme sensor.Nuclear receptors (NRs) 2 are eukaryotic transcription factors that activate or repress gene expression in response to binding small signaling molecules such as steroid hormones, lipophilic vitamins, and fatty acids (1). Genes regulated by NRs are involved in a myriad of cellular processes ranging from metabolic homeostasis to growth and development. The subjects of this article, Rev-erb␣ and Rev-erb␤, are NRs that have overlapping functions and tissue expression patterns (2-9) and are under circadian control (10 -12). Rev-erb NRs repress the transcription of key genes, e.g. Bmal1, CLOCK, and Rev-erb␣ itself, involved in regulating the molecular clock (13)(14)(15). This is accomplished in part through the formation of a heterodimeric Bmal1-CLOCK complex that activates the transcription of clock-controlled genes including Rev-erb␣/␤, completing a critical feedback loop required for circadian rhythm maintenance (6, 7). Rev-erb␣ and Rev-erb␤ also regulate the expression of genes involved in gluconeogenesis, lipid homeostasis, and immune responses, ultimately synchronizing these processes to the diurnal cycle (16 -21).The multiple functions of NRs (DNA, ligand, and coregulator binding) are accomplished through their modular structure (22, 23). The N-terminal A/B domain is hypervariable, is involved in ligand-independent transcriptional regulation, and is subject to ...

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Emerging roles of the corepressors NCoR1 and SMRT in homeostasis

Cited by 264 publications

References 122 publications

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

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