Trends in Biochemical Sciences
ReviewNuclear receptor coregulators merge transcriptional coregulation with epigenetic regulation
Section snippets
Transcriptional control by nuclear receptors and nuclear receptor coregulators
Ligand-dependent nuclear receptors (NRs) belong to the NR gene superfamily, and mediate most of the biological actions of steroid hormone-related fat-soluble ligands through transcriptional control of the NR target genes [1]. The other NR members are orphan NRs (i.e. their ligands are unknown), and their transcriptional activities are constitutively active or repressive, owing to a lack of ligand binding or dependency [2]. Like the other classes of DNA-binding transcriptional regulatory
A history of NR coregulator identification
It is well established that hormonal activation of endogenous target genes is achieved mainly at the level of transcription 7, 9. Like the other classes of DNA-binding transcription factors, transcriptional NR coregulators were initially thought to serve as NR auxiliary regulators and/or adaptors, bridging NRs and basic transcription factors at target gene promoters, and efficiently forming stable complexes of transcription initiation machinery with RNA polymerase II [5]. Indeed, using in vitro
New classes of NR coregulators: transcriptional coregulation through chromatin reorganization
Recent progress in the chromatin modification and epigenomics fields has shown that chromatin reorganization is an essential process for dynamic transcriptional control by NRs and by other classes of DNA-binding transcription factors [29]. In other words, any regulator of chromatin reorganization is a potential NR coregulator, and these factors coregulate NRs both directly and indirectly. Depending on the roles of the coregulators in chromatin reorganization, they can be classified into several
Histone modifiers are NR coregulators
Histone modifications and nucleosomal structure constitute chromatin environments that are determinants for transcriptional controls. Therefore, histone-modifying enzymes and histone chaperones are potential coregulators for NRs. Supporting this idea, histone-modifying enzymes other than HATs and HDACs, as well as histone chaperones, have recently been documented to serve as NR coregulators.
NR coregulators form complexes
Decades of intensive investigation of NR coregulators have revealed that many coactivators and corepressors are components of multisubunit coregulator complexes. Accumulating evidence also indicates that complex compositions vary in a spatial and temporal manner, and that the complex subunits are substrates for multiple PTMs. The coregulatory complexes appear to mediate crosstalk of NRs with a number of other cellular signaling pathways.
Concluding remarks
A ‘state of the art’ picture of NR coregulators, based on our interpretation of available data can now emerge (Figure 5). In the early stages of analysis (until around 2000), the major focus for the molecular dissection of NR coregulator functions was related to histone acetylation and physical mediators that bridge NRs with the basal transcriptional machinery. Fruitful descriptions of two oppositely acting enzymes, HATs and HDACs [in NCoR/SMRT (silencing mediator for retinoid or
Acknowledgements
We thank Drs H. Kitagawa and J. Yanagisawa, and the past and present members of our laboratory for sharing the information and ideas needed to build our current view. We apologize to any colleagues whose work was not cited in this review owing to space limitations.
References (98)
The nuclear receptor superfamily: the second decade
Cell
(1995)- et al.
Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation
Mol. Cell
(2007) Cracking the coregulator codes
Curr. Opin. Cell Biol.
(2008)Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer
Cell
(2009)Transcriptional inhibition by a glucocorticoid receptor-beta-galactosidase fusion protein
Cell
(1988)Distinct classes of transcriptional activating domains function by different mechanisms
Cell
(1990)Steroid hormone receptors compete for factors that mediate their enhancer function
Cell
(1989)A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors
Cell
(1996)Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase
Cell
(1997)The transcriptional coactivators p300 and CBP are histone acetyltransferases
Cell
(1996)
The role of chromatin during transcription
Cell
ACF, an ISWI-containing and ATP-utilizing chromatin assembly and remodeling factor
Cell
Chromatin challenges during DNA replication and repair
Cell
The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities
Cell
Regulation of dendritic development by neuron-specific chromatin remodeling complexes
Neuron
The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome
Cell
The mammalian epigenome
Cell
Chromatin modifications and their function
Cell
Dynamic regulation of histone lysine methylation by demethylases
Mol. Cell
Crosstalk among Histone Modifications
Cell
H2B ubiquitylation plays a role in nucleosome dynamics during transcription elongation
Mol. Cell
Catalysis and substrate selection by histone/protein lysine acetyltransferases
Curr. Opin. Struct. Biol.
Nuclear receptor function requires a TFTC-type histone acetyl transferase complex
Mol. Cell
Protein arginine methylation in mammals: who, what, and why
Mol. Cell
Histone demethylation mediated by the nuclear amine oxidase homolog LSD1
Cell
Histone deimination antagonizes arginine methylation
Cell
Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors
Cell
NAD+-dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1
Cell
Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1
Mol. Cell
Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha
Mol. Cell
SRC-3 coactivator functional lifetime is regulated by a phospho-dependent ubiquitin time clock
Cell
Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors
Curr. Opin. Genet. Dev.
Histone H3 lysine 9 methyltransferase G9a is a transcriptional coactivator for nuclear receptors
J. Biol. Chem.
Identification of the MLL2 complex as a coactivator for estrogen receptor alpha
J. Biol. Chem.
Regulation of estrogen receptor alpha by the SET7 lysine methyltransferase
Mol. Cell
JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor
Cell
Diversity within the JMJD2 histone demethylase family
Biochem. Biophys. Res. Commun.
Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3
Mol. Cell
A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation
Mol. Cell
A TFTC/STAGA module mediates histone H2A and H2B deubiquitination, coactivates nuclear receptors, and counteracts heterochromatin silencing
Mol. Cell
Orphan nuclear receptors: from gene to function
Endocr. Rev.
Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response
Genes Dev.
Coregulators: from whence came these “master genes”
Mol. Endocrinol.
Estrogen receptor null mice: what have we learned and where will they lead us?
Endocr. Rev.
Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids
Endocr. Rev.
Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex
Nature
The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion
Proc. Natl. Acad. Sci. U.S.A.
Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells
Nat. Rev. Immunol.
DNA demethylation in hormone-induced transcriptional derepression
Nature
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