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Deconstructing repression: evolving models of co-repressor action

Subjects

Key Points

  • A large number of co-repressor complexes, containing a series of different enzymatic activities, are recruited to DNA by transcription factors. Their function is to mediate chromatin remodelling and modifications of the histone tails, therefore cooperating in establishing and maintaining transcriptional repression.

  • The co-repressors nuclear receptor co-repressor (NCoR, also known as NCOR1) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT, also known as NCOR2) were originally isolated in 1995. Since then our view of the mechanism of action of co-repressors has progressively changed. Here, we describe how models of co-repressor function have evolved from a simple exchange between co-repressors and co-activators to a combinatorial model of co-repressor and co-activator action.

  • Dismissal of co-repressors from regulated promoters is important to allow co-activator recruitment and is achieved through active steps of de-repression that involve post-translational modification of the co-repressors.

  • Gene deletion studies of the NCoR and SMRT co-repressors in mouse models have indicated that they are specifically required for different developmental processes. NCoR is crucial in the development of erythrocytes and thymocytes, whereas SMRT is required for the development of the heart.

  • Transcriptional repression mediated by NCoR and SMRT is crucial in the maintenance of embryonic neural stem cells, and their absence results in differentiation down glial or glial and neuronal pathways, respectively.

Abstract

A crucial aspect of development, homeostasis and prevention of disease is the strict maintenance of patterns of gene repression. Gene repression is largely achieved by the combinatorial action of various enzymatic complexes — known as co-repressor complexes — that are recruited to DNA by transcription factors and often act through enzymatic modification of histone protein tails. Our understanding of how co-repressors act has begun to change over recent years owing to the increased availability of genome-scale data. Here, we consider specific strategies that underlie repression events — for example, those mediated by the nuclear receptor co-repressor (NCoR, also known as NCOR1) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT, also known as NCOR2) co-repressor complexes — and discuss emerging themes in gene repression.

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Figure 1: Co-repressor complexes and associated enzymatic activities.
Figure 2: Three progressive models of transcriptional regulation by HAT- and HDAC-containing complexes.
Figure 3: Co-repressor clearance by protein ubiquitylation.
Figure 4: Differential aspects of NCoR and SMRT regulation and function.

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Acknowledgements

We are grateful to J. Hightower for her help in figure preparation. We apologize to all our colleagues whose important and insightful findings could not be included in this review because of limited space. V.P. is supported by US National Institute of Diabetes and Digestive and Kidney Diseases grant K99DK078756. M.G.R. is an investigator with the Howard Hughes Medical Institute.

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Glossary

Methylation

The enzymatic process of adding a methyl group to a lysine or an arginine residue on histone tails or other proteins. Alternatively, methyl groups can be added to DNA itself on cytosine bases.

Histone

A family of small, highly conserved basic proteins that are found in the chromatin of all eukaryotic cells and that associate with DNA to form a nucleosome. Two each of the core histones H2A, H2B, H3 and H4 make up an octameric nucleosome, around which DNA winds.

Acetylation

The enzymatic process of adding an acetyl group to a lysine residue on histone tails or on other proteins.

Ubiquitylation

The enzymatic process of covalently conjugating a protein with single copies or chains of ubiquitin. Ubiquitin is an 8.5-kDa protein that exists in all eukaryotic cells.

Sumoylation

The enzymatic process of covalently conjugating a protein with the small protein SUMO.

Nuclear hormone receptors

A large family ofDNA-binding transcription factors that are responsible for sensing various hormonal and environmental stimuli and mediating gene expression accordingly.

Chromatin immunoprecipitation

A technique that is used to identify potential regulatory sequences by isolating soluble DNA chromatin extracts (complexes of DNA and protein) using antibodies that recognize specific DNA-binding proteins.

Polycomb

A class of proteins – originally described in Drosophila melanogaster – that maintain the stable and heritable repression of several genes, including the homeotic genes.

Transrepression

Transcriptional repression mediated by transcription factors that are not directly bound to DNA but are recruited to the promoter by other transcription factors.

Telencephalon

The anterior portion of the forebrain, which consists of the cerebral cortex, basal ganglia, corpus striatum and olfactory bulb.

Astroglia

Astrocytes (collectively known as astroglia) are star-shaped glial (non-nervous) cells in the brain and spinal cord that surround and support neurons and are now additionally thought to have a number of active roles in the brain.

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Perissi, V., Jepsen, K., Glass, C. et al. Deconstructing repression: evolving models of co-repressor action. Nat Rev Genet 11, 109–123 (2010). https://doi.org/10.1038/nrg2736

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