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Controlling nuclear receptors: the circular logic of cofactor cycles

Key Points

  • Nuclear receptors provide an interesting model to study transcriptional regulation and to investigate the molecular mechanisms of the ligand-dependent switch from gene repression to gene activation. In this review, we report recent advances in our understanding of nuclear-receptor-mediated transcriptional regulation by focusing on the mechanisms that regulate the switch from gene repression to gene activation and that further modulate transcriptional activity.

  • After providing a general overview of the nuclear receptor superfamily of transcription factors, we introduce the large network of coregulatory proteins that function as corepressors and coactivators to mediate nuclear-receptor-regulated transcriptional activities. As there are numerous highly modulated regulatory proteins that are associated in numerous distinct complexes, their pattern of recruitment and their enzymatic activities define a specific 'cofactor code' on the regulated promoter.

  • We review in detail several recent reports showing that the various coregulator complexes bind to the nuclear-receptor-regulated transcription unit after a precisely timed and ordered recruitment.

  • The kinetics of promoter occupancy by nuclear receptors and associated coregulators are described, focusing on the cyclical recruitment of novel receptor molecules and on the molecular strategies that regulate the exchange from corepressor to coactivators.

  • Finally, we review the multiplicity of mechanisms that permit the integration of several distinct signalling pathways at the transcriptional level through modifications of the nuclear receptors or of their associated coregulators. Three specific examples — the retinoic acid receptor (RAR), the coactivator CBP/p300 and the corepressor NCoR/SMRT — are used to illustrate possible ways of regulating each group of proteins.

Abstract

Nuclear receptors regulate many biologically important processes in development and homeostasis by their bimodal function as repressors and activators of gene transcription. A finely tuned modulation of the transcriptional activities of nuclear receptors is crucial for determining highly specific and diversified programmes of gene expression. Recent studies have provided insights into the molecular mechanisms that are required to switch between repression and activation functions, the combinatorial roles of the multiple cofactor complexes that are required for mediating transcriptional regulation, and the central question of how several different signalling pathways can be integrated at the nuclear level to achieve specific profiles of gene expression.

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Figure 1: Mechanisms of transcriptional regulation by nuclear receptors.
Figure 2: Coactivator and corepressor complexes are required for nuclear-receptor-mediated transcriptional regulation.
Figure 3: Ordered cofactor recruitment by the ER.
Figure 4: Ubiquitin-dependent exchange of corepressors for coactivators.
Figure 5: Integration of signalling pathways on nuclear-receptor-mediated transcriptional regulation.

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Acknowledgements

We sincerely thank I. Garcia Bassets and C. K. Glass for critical reading of this manuscript and for insightful discussions. We are also grateful to J. Hightower for preparation of the figures. We apologize to all our colleagues whose important and insightful findings could not be included in this review because of space limitations. M.G.R is an investigator with the Howard Hughes Medical Institute and work in the laboratory is supported by grants from the National Institutes of Health.

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DATABASES

Entrez Gene

CATD

Myc

RAR

TFF1

Swiss-Prot

AP1

AR

CARM1

CBP

CNTF

CtBP

GR

NCoA1

NCoA3

p300

PRMT1

RIP140

SMRT

SRA1

TBL1

TBLR1

Saccharomyces genome database

Ash1

HO

Swi5

FURTHER INFORMATION

Michael Rosenfeld's laboratory

NuReBaSe

Nuclear Receptor Signaling Atlas

Frank Gannon's laboratory website

Glossary

ORPHAN RECEPTOR

A subclass of nuclear receptors that were originally identified as orphans because the ligand was unknown.

ACETYLATION

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

METHYLATION

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

UBIQUITYLATION

A three-step enzymatic process that covalently conjugates the small protein ubiquitin to a Lys residue on a protein substrate. Ubiquitin can be added as a monomer or as a polymer to form long chains.

ACTIN

An abundant protein that forms filaments that are the main constituents of the cytoskeleton of all eukaryotic cells: the monomeric form is known as G-actin and the polymeric, filamentous form as F-actin.

HISTONE CODE

The post-translational modifications of histone tails usually in characteristic clusters, which include acetylation, phosphorylation, ubiquitylation, methylation and ADP-ribosylation. The modified histone tails combine to create an epigenetic code for the regulation of gene expression.

α HELIX

An element of protein secondary structure in which hydrogen bonds along the backbone of a single polypeptide cause the chain to form a right-handed helix.

CHROMATIN IMMUNOPRECIPITATION

(ChIP). A technique that is used to specifically immunoprecipitate complexes of DNA with associated proteins. The use of antibodies specific for histone modifications, DNA-binding transcription factors or coregulators has allowed the study of promoter occupancy by different factors and the state of chromatin modification.

PROTEASOME

A large protein complex that degrades intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

METABOLIC OPERON

A group of contiguous bacterial genes that are required for a metabolic function, and which are transcribed together in a single mRNA molecule.

ENHANCER

A DNA regulatory sequence that modulates the rate of transcription of a specific gene from a distance.

SUMOYLATION

The enzymatic process of adding the small SUMO protein to Lys residues on target proteins.

G1/S TRANSITION

The cell-cycle checkpoint at the transition between the Gap phase-1 (G1) and the beginning of DNA replication.

CYTOKINE

A member of a large family of secreted proteins that interact with cellular receptors. Cytokine production results in the activation of an intracellular signalling cascade that commonly regulates processes such as immune function and inflammation.

SCF E3 LIGASE COMPLEX

A multisubunit E3 ubiquitin ligase complex that contains an F-box protein for specific substrate recognition.

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Perissi, V., Rosenfeld, M. Controlling nuclear receptors: the circular logic of cofactor cycles. Nat Rev Mol Cell Biol 6, 542–554 (2005). https://doi.org/10.1038/nrm1680

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