Alternative mRNA Splicing of Corepressors Generates Variants That Play Opposing Roles in Adipocyte Differentiation

Goodson, Michael L.; Mengeling, Brenda J.; Jonas, Brian A.; Privalsky, Martin L.

doi:10.1074/jbc.m111.291625

Cited by 33 publications

(74 citation statements)

References 109 publications

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“…Mouse liver extracts were produced by homogenizing 10 mg of tissue in 2ϫ Laemmli SDS-PAGE sample buffer (62 mM Tris-Cl [pH 6.8], 10% glycerol, 2% sodium dodecyl sulfate, 5% ␤-mercaptoethanol, 0.25 mg/ml bromophenol blue). Immunoblotting was performed as previously described (16).…”

Section: Methodsmentioning

confidence: 99%

“…We reported previously that there is a change in NCoR splicing from an splice variant that possesses three RIDs, which predominates in the preadipocyte and inhibits adipose differentiation in culture when overexpressed, to a ␦ splice form that possesses two RIDs, predominates in the mature adipocyte, and enhances adipose differ-entiation when overexpressed (16). We proposed that this change in NCoR splicing serves as a key natural switch in differentiation and helps to establish the correct transcriptional program in the mature cell.…”

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confidence: 99%

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Alteration of NCoR Corepressor Splicing in Mice Causes Increased Body Weight and Hepatosteatosis without Glucose Intolerance

Goodson

Young

Snyder

et al. 2014

Molecular and Cellular Biology

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Alternative mRNA splicing is an important means of diversifying function in higher eukaryotes. Notably, both NCoR and SMRT corepressors are subject to alternative mRNA splicing, yielding a series of distinct corepressor variants with highly divergent functions. Normal adipogenesis is associated with a switch in corepressor splicing from NCoR to NCoR␦, which appears to help regulate this differentiation process. We report here that mimicking this development switch in mice by a splice-specific whole-animal ablation of NCoR is very different from a whole-animal or tissue-specific total NCoR knockout and produces significantly enhanced weight gain on a high-fat diet. Surprisingly, NCoR ؊/؊ mice are protected against diet-induced glucose intolerance despite enhanced adiposity and the presence of multiple additional, prodiabetic phenotypic changes. Our results indicate that the change in NCoR splicing during normal development both helps drive normal adipocyte differentiation and plays a key role in determining a metabolically appropriate storage of excess calories. We also conclude that whole-gene "knockouts" fail to reveal how important gene products are customized, tailored, and adapted through alternative mRNA splicing and thus do not reveal all the functions of the protein products of that gene.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Alteration of NCoR Corepressor Splicing in Mice Causes Increased Body Weight and Hepatosteatosis without Glucose Intolerance

Goodson

Young

Snyder

et al. 2014

Molecular and Cellular Biology

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“…The C-terminus of co-repressor proteins contains three RIDs that are characterized by a presence of CoRNR box, which is essential for NR-binding as outlined above (Hu & Lazar 1999, Nagy et al 1999, Perissi et al 1999. The exons encoding RIDs are subject to alternative splicing that produces different co-repressor isoforms, which are expressed in a tissue-specific manner (Faist et al 2009, Goodson et al 2011, Malartre et al 2004. Interestingly, amino acid sequences of specific RIDs dictate the preferential binding to different NRs, with most N-terminal of the RIDs (N3 in NCoR and S3 in SMRT) having the highest avidity for TR, while S2 has demonstrated preference for the retinoic acid receptor (RAR) , Cohen et al 2000, Makowski et al 2003, Webb et al 2000.…”

Section: Structural and Functional Domains Of Co-regulator Proteinsmentioning

confidence: 99%

“…1C). As outlined above, both NCoR and SMRT have three C-terminal RIDs, that preferentially bind different NRs , Cohen et al 2000, Faist et al 2009, Goodson et al 2011, Makowski et al 2003, Malartre et al 2004, Webb et al 2000. This feature makes targeting of specific RID an attractive strategy to address the role of co-repressors in the action of specific NRs as well as physiological significance of different co-repressor isoforms.…”

Section: Animal Models Of Co-regulator Functionmentioning

confidence: 99%

“…It has been shown that adipogenesis in mice is associated with a switch in co-repressor splicing from NCoRω carrying all three RID domains, which represses adipogenesis, to NCoRδ where only RID2 and RID1 are present, which appears to support a pro-adipogenic program (Goodson et al 2011). Consistent with the adipocyte-specific NCoR knockout phenotype, whole-body expression of the pro-adipogenic NCoRδ isoform results in protection from glucose intolerance despite increased weight gain and adiposity, as well as hepatic steatosis on a high-fat diet (Goodson et al 2014).…”

Section: Ncor In Adipose Tissue: Adipocyte-specific and Ncorω Knockoutmentioning

confidence: 99%

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Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

Astapova¹

2016

Journal of Molecular Endocrinology

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Thyroid hormone (TH) controls a wide range of physiological processes through TH receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine (T 3 )-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T 3 binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T 3 target genes and hypothalamic-pituitary-thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T 3 , local chromatin structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis.

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NCOR1—a new player on the field of T cell development

Müller

Hainberger

Stolz

et al. 2018

Journal of Leukocyte Biology

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Nuclear receptor corepressor 1 (NCOR1) is a transcriptional corepressor that links chromatin-modifying enzymes with gene-specific transcription factors. Although identified more than 20 years ago as a corepressor of nuclear receptors, the role of NCOR1 in T cells remained only poorly understood. However, recent studies indicate that the survival of developing thymocytes is regulated by NCOR1, revealing an essential role for NCOR1 in the T cell lineage. In this review, we will briefly summarize basic facts about NCOR1 structure and functions. We will further summarize studies demonstrating an essential role for NCOR1 in controlling positive and negative selection of thymocytes during T cell development. Finally, we will discuss similarities and differences between the phenotypes of mice with a T cell-specific deletion of NCOR1 or histone deacetylase 3 (HDAC3), because HDAC3 is the predominant member of the HDAC family that interacts with NCOR1 corepressor complexes. With this review we aim to introduce NCOR1 as a new player in the team of transcriptional coregulators that control T cell development and thus the generation of the peripheral T cell pool.

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Alternative mRNA Splicing of Corepressors Generates Variants That Play Opposing Roles in Adipocyte Differentiation

Cited by 33 publications

References 109 publications

Alteration of NCoR Corepressor Splicing in Mice Causes Increased Body Weight and Hepatosteatosis without Glucose Intolerance

Alteration of NCoR Corepressor Splicing in Mice Causes Increased Body Weight and Hepatosteatosis without Glucose Intolerance

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

NCOR1—a new player on the field of T cell development

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