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Expression data from 3T3-MEFs derived from wild-type and SMRT RID mutant mice

ABSTRACT: SMRT (silencing mediator of retinoid and thyroid hormone receptors) is recruited by numerous transcription factors to mediate lineage and signal dependent transcriptional repression. We generated a knock-in mutation in the receptor interaction domain (RID) of SMRT (SMRTmRID) that solely disrupts its interaction with nuclear hormone receptors. SMRTmRID-derived 3T3-MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. We measured global gene expression in wild-type versus SMRTmRID-derived 3T3-MEFs in the undifferentiated state to examine which pathways were altered. Our results demonstrate that SMRT-RID dependent repression is a key determinant of the adipogenic set point. Keywords: SMRTmRID expression compared to wild-type

ORGANISM(S): Mus musculus

PROVIDER: GSE13143 | GEO | 2009/01/07

SECONDARY ACCESSION(S): PRJNA109577

REPOSITORIES: GEO

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Transcription profiling of mouse 3T3-MEFs derived from wild-type and SMRT RID mutants

Project description:SMRT (silencing mediator of retinoid and thyroid hormone receptors) is recruited by numerous transcription factors to mediate lineage and signal dependent transcriptional repression. We generated a knock-in mutation in the receptor interaction domain (RID) of SMRT (SMRTmRID) that solely disrupts its interaction with nuclear hormone receptors. SMRTmRID-derived 3T3-MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. We measured global gene expression in wild-type versus SMRTmRID-derived 3T3-MEFs in the undifferentiated state to examine which pathways were altered. Our results demonstrate that SMRT-RID dependent repression is a key determinant of the adipogenic set point. Experiment Overall Design: 3T3 cells derived from wild-type and SMRT RID MEFs were cultured under pre-differentiated conditions prior to harvesting for RNA.

2009-01-18 | E-GEOD-13143 | biostudies-arrayexpress

SMRT-RID mutation linked to Type I Pneumocyte Associated Respiratory Distress Syndrome via TR repression

Project description:We show that knock-in mutations of the nuclear corepressor SMRT in C57Bl6 mice (SMRTmRID) produces a novel respiratory distress syndrome (RDS) due to prematurity of the type I pneumocyte. Treatment with the anti-thyroid hormone drug, propylthiouracil (PTU), completely rescues the SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which in turn appears to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRTmRID phenotype. These results identify a second nuclear receptor, the TR, in type I pneumocyte differentiation and suggest a new type of therapeutic option in the treatment of glucocorticoid non-responsive RDS. Total RNA was obtained from WT and SMRT-RID E18.5 lungs of embryos from mothers treated with Diet containing 0.15% PTU or control chow for 2 days (from E16.5).

2011-10-13 | E-GEOD-30661 | biostudies-arrayexpress

NCoR1, SMRT, Polymerase II and input ChIP-Seq

Project description:ChIP-seq of mouse embryonic fibroblast-adipose like cell line 3T3-L1 to identify binding sites of NCoR1 and SMRT following induction of differentiation, and RNA Pol-II after SMRT knock down

2012-04-23 | E-MTAB-1031 | biostudies-arrayexpress

CDDP treatment of U2OS cells with NCOR and SMRT knock-down

2012-02-06 | GSE34226 | GEO

CDDP treatment of U2OS cells with NCOR and SMRT knock-down

Project description:We detected an interaction between checkpoint kinase Chk2 and some members of the NCOR/SMRT co-repressor complex. In order to study the role of gene repression in the checkpoint response to DNA damage, we performed RNA profiling in NCOR or SMRT knockdown cells after treztment with cisplatin. U2OS cells were transfected with siRNAs for NCOR or SMRT, grown for 2 days in complete medium, and then treated with 100 microM cisplatin (CDDP) for 6h. Biological duplicates were used for RNa profiling

2012-02-06 | E-GEOD-34226 | biostudies-arrayexpress

Mus musculus

Project description:Expression data from 3T3-MEFs derived from wild-type and SMRT RID mutant mice

| PRJNA109577 | ENA

NCoR1 and SMRT play unique roles in thyroid hormone signaling in the liver

Project description:NCoR1 (Nuclear receptor Co-Repressor) and SMRT (Silencing Mediator of Retinoid and Thyroid hormone receptor) are well-recognized coregulators of nuclear receptor (NR) action. However, their unique roles in the regulation of thyroid hormone (TH) signaling in specific cell types have not been determined. To accomplish this we generated a mouse model that lacked function of either NCoR1 or SMRT or both in the liver only. Despite both corepressors being present in the liver, SMRT had no ability to regulate TH signaling when deleted in either euthyroid or hypothyroid animals. In contrast, disruption of NCoR1 action confirmed that it is the principal mediator of TH sensitivity in vivo. While SMRT played little role in TH signaling alone, when disrupted in combination with NCoR1 it greatly accentuated the activation of hepatic lipogenesis regulated by NCoR1. Thus, corepressor specificity exists in vivo and NCoR1 is the principal regulator of TH action in the liver. However, both NCoR1 and SMRT collaborate to control hepatic lipogenesis and lipid storage, which likely reflects their cooperative activity in regulating the action of multiple NRs including the thyroid hormone receptor (TR). RNA was extracted from livers from 3 individual mice for each group (Double-floxed, Liver specific-SMRT knock out, and Liver specific-double knock out); all were euthyroid, female mice

2014-11-21 | E-GEOD-54192 | biostudies-arrayexpress

SMRT regulates metabolic homeostasis and adipose tissue macrophage phenotypes in tandem

Project description:The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) is a nuclear corepressor that regulates the transcriptional activity of many transcription factors critical for metabolic processes. While the importance of SMRT’s role in the adipocyte has been well-established, prior mouse models have yielded contradictory phenotypes, limiting our understanding of its in vivo function in the context of homeostatic maintenance. Multiple models suggest that SMRT deficiency leads to increased adiposity, though the effects of SMRT loss on glucose tolerance and insulin sensitivity have been variable. We therefore generated an adipocyte-specific SMRT knockout (adSMRT-/-) mouse to more clearly define SMRT’s metabolic contributions. In doing so, we found that SMRT deletion in the adipocyte does not, in fact, lead to obesity, despite increased food consumption in knockouts – even when mice are challenged with a high-fat diet. This suggests that prior adiposity phenotypes described in generalized models were due to effects beyond the adipocyte. However, an adipocyte-specific SMRT deficiency still led to dramatic effects on systemic glucose tolerance and adipocyte insulin sensitivity, impairing both. This metabolically deleterious effect was coupled with a surprising immune phenotype, wherein most genes differentially expressed in the adipose tissue of adSMRT-/- mice were upregulated in pro-inflammatory pathways. Flow cytometry and conditioned media experiments demonstrated that secreted factors from knockout adipose tissue strongly informed resident macrophages to develop a pro-inflammatory, MMe (metabolically activated) phenotype. Taken together, these studies suggest a novel role for SMRT as an integrator of metabolic and inflammatory signals to effectively maintain physiological homeostasis.

2019-07-05 | GSE129369 | GEO

NCoR1 and SMRT play unique roles in thyroid hormone signaling in the liver

2014-11-21 | GSE54192 | GEO

RNAseq from Mfn1/2 knockout MEFs with adipogenic differentiation

Project description:Objective: A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells. Methods: We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA. Results: Mfn1-/- MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile including Pparg upregulation. Mfn2-/- MEFs also had a disrupted mitochondrial morphology, but in contrast to Mfn1-/- MEFs they showed reduced expression of adipocyte markers. Mfn1 and Mfn2 siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings. Conclusions: Loss of Mfn1 but not Mfn2 in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.

2023-06-01 | GSE232502 | GEO

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