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Review
. 2023 Oct 2;13(10):1477.
doi: 10.3390/biom13101477.

REST Is Not Resting: REST/NRSF in Health and Disease

Lili Jin  1 , Ying Liu  2 , Yifan Wu  2 , Yi Huang  2 , Dianbao Zhang  2
Affiliations
Review

REST Is Not Resting: REST/NRSF in Health and Disease

Lili Jin et al. Biomolecules. .

Abstract

Chromatin modifications play a crucial role in the regulation of gene expression. The repressor element-1 (RE1) silencing transcription factor (REST), also known as neuron-restrictive silencer factor (NRSF) and X2 box repressor (XBR), was found to regulate gene transcription by binding to chromatin and recruiting chromatin-modifying enzymes. Earlier studies revealed that REST plays an important role in the development and disease of the nervous system, mainly by repressing the transcription of neuron-specific genes. Subsequently, REST was found to be critical in other tissues, such as the heart, pancreas, skin, eye, and vascular. Dysregulation of REST was also found in nervous and non-nervous system cancers. In parallel, multiple strategies to target REST have been developed. In this paper, we provide a comprehensive summary of the research progress made over the past 28 years since the discovery of REST, encompassing both physiological and pathological aspects. These insights into the effects and mechanisms of REST contribute to an in-depth understanding of the transcriptional regulatory mechanisms of genes and their roles in the development and progression of disease, with a view to discovering potential therapeutic targets and intervention strategies for various related diseases.

Keywords: REST/NRSF; cancer; chromatin modification; development; transcriptional regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Gene structure and protein structure of REST. (A) Human REST is located in Chromosome 4q12, and it has five exons. The exon 5 was found to be mutually exclusive of exon 4. (B) The full-length human REST consists of 1097 aa, and there is a DNA binding domain (DBD), an N-terminal repressor domain (NRD), and a C-terminal repressor domain (CRD) for its regulatory activities. ZF indicates zinc finger. (C) The protein structure was predicated using Alphafold2.
Figure 2
Figure 2
REST modulates gene activation via histone modification. REST binds to the RE1 motif within target genes and recruits Sin3A/B and CoREST as beacons for the recruitment of coregulators to form regulatory complexes. The chromatin was silenced via histone 3/4 deacetylation by HDACs, H3K9 methylation by G9a and SUV39H1, and H3K4 demethylation by LSD1 and H4K8 acetylation by BRG1. Further, the H3K36 methylation mediated by Tet1/3 might activate gene transcription.
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This research was funded by the National Natural Science Foundation of China, grant numbers 81703102 and 82073419.

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