Review
Nuclear receptor coregulators merge transcriptional coregulation with epigenetic regulation

https://doi.org/10.1016/j.tibs.2011.01.001Get rights and content

Members of the nuclear steroid/thyroid hormone receptor (NR) gene superfamily are DNA-binding transcription factors that regulate target genes in a spatiotemporal manner, depending on the promoter context. In vivo observations of ligand responses in NR-mediated gene regulation led to the identification of ligand-dependent coregulators that directly interact with NRs. Functional dissection of NR coregulators revealed that their transcriptional coregulation was linked to histone acetylation. However, recent work in the fields of reversible histone modification and chromatin remodeling indicates that histone-modifying enzymes, including histone methylases and chromatin remodelers, are potential transcriptional coregulators that interact directly and indirectly with NRs.

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.

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