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Chromatin crosstalk in development and disease: lessons from REST

Key Points

  • Enzymes that modify chromatin have an important role in the regulation of gene transcription. Often, these enzymes exist in the cell as part of larger complexes with other enzymes that provide complementary activities. Studies of the corepressor complexes that are recruited by the repressor element 1-silencing transcription factor (REST) have helped to identify functional interdependencies of some of these enzymes.

  • REST can recruit multiple corepressor complexes through independent domains resulting in either short-term transcriptional repression or long-term gene silencing. Recruitment of some complexes is cell- and gene-specific, whereas recruitment of others is influenced by intracellular signals.

  • Perturbation of REST is associated with several human diseases, including some neuronal and cardiovascular disorders, and cancer.

  • Bioinformatic analysis has predicted a genome-wide set of REST-binding sites and a comprehensive list of potential target genes. These data have been used successfully to predict some REST functions and identify potential therapeutic targets for REST-associated diseases.

  • Investigations of REST and its associated corepressors have provided insight into the coordination of enzymatic activities that modify chromatin and affect gene transcription. These studies make significant contributions to our understanding of chromatin changes and gene regulation in health and disease.

Abstract

Protein complexes that contain chromatin-modifying enzymes have an important role in regulating gene expression. Recent studies have shown that a single transcription factor, the repressor element 1-silencing transcription factor (REST), can act as a hub for the recruitment of multiple chromatin-modifying enzymes, uncovering interdependencies among individual enzymes that affect gene regulation. Research into the function of REST and its corepressors has provided novel insight into how chromatin-modifying proteins cooperate, and how alterations in this function cause disease. These mechanisms will be relevant to the combinatorial functioning of modular transcriptional regulators that work together to regulate a common promoter; they should also identify targets for potential therapies for a range of human diseases.

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Figure 1: REST corepressors.
Figure 2: Histone modifications and the repressor element 1-silencing transcription factor (REST) complex.

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Acknowledgements

We thank J. Boyes for helpful comments and discussions on the manuscript. Work in the Wood laboratory is supported by the British Heart Foundation and the European Commission.

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DATABASES

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Huntington disease

von Hippel–Lindau syndrome

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RE1 database from REF 91

RE1 database from REF 87

RE1 database from REF 93

 RE1 database from REF 94

Glossary

Regulated secretion

A process by which proteins and neurotransmitters are stored in secretory vesicles and released only in response to external stimuli such as hormones.

Hippocampus

An anatomical region of the brain, with a shape likened to that of a seahorse, that is located adjacent to the ventricles and is important for memory formation.

Ischaemia

An insufficient supply of blood to an organ, often resulting from an artery blockage or constriction.

AMPA receptors

Ligand-gated cation channels that are responsive to excitatory amino acids such as glutamate, and are composed of four individual subunits as a homo- or heterotetramer. The presence of the glutamate receptor 2 (GluR2) subunit prevents the permeation of calcium through the channel.

Inhibitory interneurons

Local circuit neurons that form connections with other neurons and release inhibitory neurotransmitters such as GABA (γ-aminobutyric acid), which act to suppress activity of the target neuron.

Striatum

A subcortical anatomical region of the brain, named for its striated appearance, that is important in coordination of movement.

Neural crest

An embryological region of dividing cells that lies adjacent to the neural tube. Cells from the neural crest migrate away and ultimately give rise to many cell types, including the neurons and glia of the peripheral nervous system, skeletal muscle and smooth muscle cells, and chromaffin cells.

Constitutive secretion

A process by which proteins and neurotransmitters are secreted by exocytosis without any requirement for external stimuli.

In-stent restenosis

The narrowing of an artery caused by the insertion of a metal cylinder (stent) intended to increase the diameter of a blocked artery, most often the result of vascular smooth muscle cell proliferation.

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Ooi, L., Wood, I. Chromatin crosstalk in development and disease: lessons from REST. Nat Rev Genet 8, 544–554 (2007). https://doi.org/10.1038/nrg2100

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