MinireviewRegulation of the cholinergic gene locus by the repressor element-1 silencing transcription factor/neuron restrictive silencer factor (REST/NRSF)
Introduction
The ability of a cell to regulate its phenotype is dependent upon its ability to carefully and precisely control which genes are expressed and which are not. In the case of neurons there are many genes whose expression is necessary to produce a neuronal phenotype, but whose expression outside the central nervous system is not needed and likely to be detrimental. Recent evidence suggests that one mechanism utilized to prevent expression of neuronal genes outside the central nervous system is that of gene repression. This review focuses on the regulation of one neuron specific gene locus, the cholinergic gene locus, by transcriptional repression. In addition to describing the regulation of the cholinergic gene locus, the complexity of this system, its application to other neuronal genes, and the many questions yet to be answered are noted.
Cholinergic neurotransmission in the central nervous system is a key process dependent on the coexpression of proteins involved in the synthesis, storage, and release of the neurotransmitter acetylcholine (ACh). ACh plays an important role in fundamental brain processes such as memory, learning, and sleep Karczmar, 1976, Bartus et al., 1982, Aigner and Mishkin, 1986. ACh is used in a cyclic process involving the uptake of choline by a high-affinity uptake system (Jope, 1979), the formation of ACh through acetylation of choline catalyzed by the enzyme choline acetyltransferase (ChAT) (EC 2.3.1.6) and the transport of ACh into synaptic vesicles by the vesicular ACh transporter (VAChT). Upon stimulation, synaptic vesicles fuse with the plasma membrane and release ACh, which can then be hydrolyzed by acetylcholinesterase to produce free choline, thereby completing the cycle.
The cholinergic gene locus is comprised of both the choline acetyltransferase gene as well as the vesicular acetylcholine transporter gene, the latter being located within the first intron of the ChAT gene. ChAT is primarily if not exclusively a cytosolic protein whereas VAChT has 12 transmembrane domains and is integrated in the membrane of synaptic vesicles. In the CNS, ChAT and VAChT are both required for cholinergic neurotransmission. In some neurodegenerative disorders, i.e. Alzheimer's disease, amyotrophic lateral sclerosis, and schizophrenia, there is a dysfunction of central cholinergic neurons involving a loss of, or abnormality in, basal forebrain ChAT activity Davies and Maloney, 1976, Coyle et al., 1983, Price, 1986, Wu and Hersh, 1994.
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Genomic structure and transcription of the cholinergic gene locus
The genes for mouse Misawa et al., 1992, Pu et al., 1993, rat Brice et al., 1989, Ishii et al., 1990, and human ChAT Kong et al., 1989, Hersh et al., 1993 have been isolated and shown to contain three 5′-noncoding exons; exon 1, referred to as the R exon; exon 2, referred to as the N exon; and exon 3, referred to as the M exon Misawa et al., 1992, Kengaku et al., 1993, Fig. 1. The alternative splicing of these three exons results in multiple 5′-mRNA species, which are transcribed from three
Coordinate regulation of ChAT and VAChT gene expression
The organization of the cholinergic gene locus suggested the possibility of coordinate regulation of the ChAT and VAChT genes at the transcriptional level Berrard et al., 1995, Berse and Blusztajn, 1995, Erickson et al., 1994, Shimojo et al., 1998. Prior to the discovery of the gene structure within the cholinergic gene locus, several studies reported that ChAT activity was regulated by growth factors Hefti et al., 1986, Gould and Butcher, 1989, Saadat et al., 1989, Knusel et al., 1991 and
Transcriptional regulation of cholinergic gene locus by REST/NRSF
Studies from a number of laboratories suggest that the transcriptional regulation of the ChAT and VAChT genes involves multiple cell specific regulatory elements. The region of the cholinergic gene locus upstream of the R-type promoter contains a consensus repressor element-1 (RE-1)/neuron-restrictive silencer element (NRSE) sequence and a cholinergic specific enhancer that presumably operate in a cooperative manner to control cholinergic gene expression in the CNS, Fig. 1. The RE-1/NRSE is a
Regulation of REST/NRSF function by its REST4 isoform
The finding that REST4 can block REST/NRSF repressor activity, coupled with REST4 expression in neuronal cells, can account for the presence of REST/NRSF in neurons without neuronal gene expression being repressed. Palm et al. (1998) reported the presence of REST/NRSF in adult neurons, albeit at rather low levels relative to its expression in non-neuronal cells. It was suggested that the inability of REST/NRSF to repress gene expression in neuronal cells could be explained by its low
Role of zinc finger domains of REST/NRSF
REST/NRSF contains nine Cys2-His2 type zinc finger domains, the first of these is near the N-terminus and is followed by a cluster of seven zinc finger domains, with the last zinc finger domain being near the C-terminus of the molecule, Fig. 2. REST4, being a truncated form of REST/NRSF contains only zinc finger domains 1–5, Fig. 2. It binds weakly to the RE-1/NRSE with the strength of binding dependent on the number of zinc finger domains present (Lee et al., 2000). These findings suggest that
REST/NRSF Repressor Domains
REST/NRSF is a modular protein that represses neuronal gene expression via two distinct repressor domains. Repression through an amino terminal domain is mediated by a Sin3-histone deacetylase (HDAC) complex, which affects chromosomal structure by promoting histone deacetylation Tapia-Ramirez et al., 1997, Grimes et al., 2000, Huang et al., 1999, Roopra et al., 2001, Naruse et al., 1999. The other repressor domain is found in the carboxyl-terminal domain and binds a novel protein, CoREST and
The future for REST
It is evident that the regulation of neuronal gene expression by REST/NRSF and its truncated isoforms is complex and far from understood. As noted above REST mediated gene repression involves two distinct repressor domains, one binding Sin3A and the other binding CoREST. Why two distinct repressor domains are present in REST/NRSF is puzzling. It is unclear whether both domains are utilized simultaneously or represent different modes of gene regulation that are utilized differentially. The need
Acknowledgements
This work was supported in part by grants AG46734 and AG05893 from the National Institutes of Health.
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2021, Journal of Biological ChemistryThe transcription factor REST up-regulates tyrosine hydroxylase and antiapoptotic genes and protects dopaminergic neurons against manganese toxicity
2020, Journal of Biological ChemistryCitation Excerpt :Recent studies have demonstrated that REST is increased in normal aging brains, preserving neuronal function and protecting against neurodegeneration through the repression of stress- and apoptosis-promoting genes (13). REST is an essential mammalian zinc finger transcriptional regulator (34) playing a variety of cellular functions, such as neurogenesis, differentiation, axonal growth, vesicular transport, and release, as well as ionic conductance (35–38). REST represses neuronal genes in non-neural cells by binding to a DNA sequence motif known as repressor element 1 (RE1; also known as NRSE) (36, 39, 40).
Pharmacological intervention of histone deacetylase enzymes in the neurodegenerative disorders
2020, Life SciencesCitation Excerpt :Apart from these modifications, some transcription factors also bring remodeling of chromatin in neurodegeneration. Two major gene silencing complexes, REST and polycomb proteins were viewed as the chromatin remodelers in the brain through histone acetylation and methylation effects on synaptic vesicles protein, channels, and adhesion proteins [14,15]. These chromatin-associated modifications were highly regulated in neurological disorders, which alter transcriptional regulation along with gene expression [16].
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2015, Life SciencesCitation Excerpt :Finally, we also observed that the cholinergic synthetic enzyme acyltransferase was also significantly diminished in sensory nerve lysates. REST has been studied with relation to its modulatory effect on cholinergic expression and function [21–25]. For example, REST alteration causes defects in cholinergic function without alteration of cell contents in Huntington's disease [26].
Rest represses maturation within migrating facial branchiomotor neurons
2015, Developmental BiologyNeuron-restrictive silencer factor functions to suppress Sp1-mediated transactivation of human secretin receptor gene
2013, Biochimica et Biophysica Acta - Gene Regulatory MechanismsCitation Excerpt :To understand further the spatial and temporal expression of hSCTR, in this report, we sought to investigate the functions of a putative neuron restrictive silencer element (NRSE) located downstream (− 83 to − 67, relative to ATG) of the hSCTR core promoter. NRSE, also known as repressor element-1 (RE-1) with a consensus sequence “NTYAGMRCCNNRGMSAG” [11], was initially identified to regulate a number of neuron-specific genes by repressing their expressions in non-neural tissues [12]. Recently, NRSE is regarded a common repressor element as it can suppress an increasing number of non-neuronal genes.