REST contributes to genome-wide epigenetic changes and is implicated in schizophrenia
. The aberrant increase of REST at the Grin2b promoter caused deficient synaptic physiology and PFC-dependent cognitive dysfunction, a hallmark of schizophrenia
. THP2 is the rate-limiting enzyme for 5-HT, and it is under the regulation of REST
. The mood-stabilizing drugs lithium and sodium valproate have been shown to regulate REST expression
. miR-9 targeted REST and PDYN, and miR-9 was targeted by REST
. REST was elevated in care-augmented rats, and its target CRH was inhibited
. The compound C737 mimics the helical structure of REST to regulate target genes involved in neuronal function and pain modulation and reduce stress-induced weight loss in female Tupaia
. REST signaling contributes to stress resilience
. The improvement in diabetes mellitus-related cognitive impairment by 9-PAHSA was mediated by REST
REST regulates heart development, structure, and function
[113]. During embryonic heart development, the elevated REST inhibited an embryonic cardiac gene HCN4
[114][115][116][117]. The training-induced REST contributes to the pathological heart rate adaptation to exercise training by reducing HCN4
[118]. REST chronically represses T channels in cardiomyocytes
[119]. REST also maintains low alpha 1H expression
[120] and regulates CACNA1H encoding alpha-subunit of Cav3.2
[121], thereby regulating aldosterone and cortisol production, which are independent predictors of mortality risk for heart failure patients. Gαo, an inhibitory G protein encoded by GNAO1, was regulated by REST. In several mouse models of heart failure, Gαo is decreased in the ventricles, leading to increased surface sarcolemmal L-type Ca
2+ channel activity and impairing Ca
2+ handling in ventricular myocytes, resulting in cardiac dysfunction
[122].
3.2. Pancreas
REST is absent in insulinoma, insulin- and glucagon-producing cells
[123]. Similar to neuronal differentiation, REST is expressed in pancreas progenitors and decreased in differentiated endocrine cells
[124]. RE1 motif was found within various genes involved in pancreas development, including pdx-1, Beta2/NeuroD, and pax4
[125]. Cx36 is also controlled by REST in insulin-producing cells
[126]. In addition, the rs2518719 SNP could alter the RE1 motif involving pancreatic neuroendocrine tumor progression
[127]. It was revealed that the REST silencing could induce human amniotic fluid-derived stem cells (hAFSCs) and bone marrow-derived mesenchymal stem cells (bmMSCs) to differentiate into insulin-producing cells
[128][129].
3.3. Skin
REST is expressed in skin keratinocytes, and NRP1 was found to be under its regulation to promote cell migration by blocking the inhibition of semaphorin 3A
[130]. During the early neural crest stage, REST is essential for melanoblast development
[131]. In melanoma, the decreased REST/RE1 activity leads to aberrant metabotropic glutamate receptor 1 (mGluR1) expression, whose ectopic expression in mouse melanocytes was sufficient to induce melanoma development
[132]. These findings provide valuable insights into the functions of REST in the skin, although much more research is needed to fully understand its role in skin biology and pathology.
3.4. Eye
The eye, being a specialized structure derived from the skin, also relies on the proper regulation of REST. In REST cKO mice generated by the Sox1-Cre allele and the floxed REST gene, REST was excised in the early neural tissues, including the lens and retinal primordia. The slightly reduced proliferation of lens epithelial cells after birth was observed, and vacuoles formed without inducing cell apoptosis. The augmented Notch signaling and the reduced lens fiber regulator genes may contribute
[133]. The REST-like gene in Drosophila was named Chn, and it promotes D1 for photoreceptor cell development
[134].
3.5. Vascular
In vascular tissue, REST was found to regulate the proliferation of vascular smooth muscle cells by targeting the K(Ca)3.1 (IKCa) potassium channel. REST was downregulated when there was cellular proliferation, indicating an inverse relationship with IKCa
[135]. In addition, REST declines in the medial smooth muscle of atherosclerotic carotids, and REST overexpression inhibits smooth muscle migration. Inhibition of REST and overexpression of IKCa determine smooth muscle and matrix content of atherosclerotic lesions
[136].
4. REST in Cancer
4.1. Nervous System Cancer
The dysregulation of REST was found in various nervous system cancers, often playing promoting roles. In neuroblastoma cells, REST was found to be reduced during differentiation
[137]. REST was downregulated in mouse neuroblastoma, leading to increased neurite length
[138]. It was found that the loss of lncRNA neuroblastoma-associated transcript-1 (NBAT-1) contributed to aggressive neuroblastoma by activating REST
[139]. REST is highly expressed in glioma, and its interference inhibits tumors
[140]. REST mediated the inhibition of proliferation of glioma by pioglitazone
[141]. In medulloblastoma, REST promotes cancer progression via epigenetic modification and AKT activation
[142]. The abnormal expression of REST in NSCs blocks their differentiation and promotes medulloblastoma formation
[143]. The transient expression of a competitive form of REST, REST-VP16, inhibited medulloblastoma
[144][145].
4.2. Non-Nervous System Cancer
The regulation pattern of REST varies in different types of lung cancers. In small-cell lung cancer cells (SCLCs), A splice variant of REST with a 50-bp insert predicting a truncated REST was highly expressed
[146]. The decreased REST permits its target gene expression, including glycine receptor alpha1 (GLRA1) subunit, migration-promoting gene ITPKA
[147][148][149], leading to de-regulation of AKT activation, promoting malignant progression
[150]. The altered REST splicing was found to mediate the anti-tumor effects of SRRM4 targeting in SCLC
[151]. Further, miR-9 inhibits the proliferation and migration of lung squamous cell carcinoma cells by blocking REST/EGFR signaling
[152]. However, in neuroendocrine lung cancer, REST mediates neuroendocrine to non-neuroendocrine fate switch to play a pro-tumorigenic role
[153]. REST-regulated SCG3 provides a sensitive prognostic biomarker for neuroendocrine lung cancer
[154].
5. Conclusion
REST is a key transcription regulator that primarily governs gene transcription via the modification of chromatin. REST plays vital roles in both physiological and pathological processes within the nervous system as well as other non-nervous systems. The imbalance of REST dynamic regulation often leads to dysplasia or diseases. Therefore, it is necessary to conduct in-depth research on its involvement in different diseases and the underlying mechanisms is imperative to gain novel insights into potential interventions for related diseases.