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FLASH GENE

Symbol

REST

contributors: mct/shn - updated : 30-03-2016

HGNC name	RE1-silencing transcription factor
HGNC id	9966

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	nine ZnF motifs (one of them is at its C-terminus)
	two repressor domains at N and C termini, with a single C terminal zinc finger motif repressing the neural specific type II sodium channel
	a HXPR motif
	one lys-rich region, one pro-rich region and two repression domains at its C- and N- termini, respectively

secondary structure

AA cysteine 397 (Cys397) plays important roles in the global folding of REST multiple ZnFs domain

HOMOLOGY

interspecies	ortholog to Rest, Mus musculus
	ortholog to Rest, Rattus norvegicus
	ortholog to rest, Danio rerio
	ortholog to C-elegans Spr-4

Homologene

FAMILY

Kruppel-type zinc finger transcription factor

CATEGORY

regulatory , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,nucleus

basic FUNCTION	a negative transcriptional regulator that restricts neuronal gene expression to neurons
	required to repress neuronal gene expression in extra neural and undifferentiated neural tissues
	may act as a master negative regular of neurogenesis
	transcriptional repressor acting at the terminal stage of the neuronal differentiation pathway and blocking the transcription of several differentiation genes
	may be an element of the interconnected regulatory network that maintains the self-renewal and pluripotency of embryonic stem cells
	acting as a transcriptional repressor in the neuronal differentiation pathways in non-neuronal cells, and playing an important role in neuronal development
	regulates TRP1 gene expression and causes changes in the levels of calcium entry through SOCCs (stimulated store-operated Ca(2+) channel (SOCC)-mediated Ca(2+) entry)
	zinc finger protein that regulates gene expression throughout the body
	a key transcriptional regulator of the fetal cardiac gene program and has a role in maintaining normal cardiac structure and function
	interplay between REST and Sp1 determines the cell-specific expression of REST target genes
	recruits small CTD phosphatases to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells
	in the CNS, functions as not only a key transcriptional repressor but also an activator for neuron-specific genes in the non-neuronal cells by specifically interacting with neuron-restricted silencer element
	plays a role as a switch regulating potassium channel expression and consequently the phenotype of vascular smooth muscle cells and human vascular disease
	master transcription factor that plays a critical role in embryo development, especially during the process of neurogenesis and neural plasticity
	a human tumour suppressor in epithelial tissues
	a key target in beta-TRCP-driven transformation and the beta-TRCP-REST axis is a new regulatory pathway controlling neurogenesis
	maintains the self-renewal and pluripotency of of embryonic stem cells
	remotely represses activity-dependent gene transcription, the level of which controls the magnitude of the repression
	REST-mediated repression of microRNAs directs the essential switch of chromatin regulatory complexes
	hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in Huntington disease
	significant role of REST in breast cancer and the reduced expression of REST might contribute to the breast cancer pathogenesis
	negative regulator of gene expression restricting the expression of neuronal genes to the nervous system
	may act as an important modulator of malignant progression in small-cell lung cancer
	transcriptional repressor REST preventing progenitors from undergoing differentiation
	novel role for REST in preventing premature expression in RPCs (retinal progenitor cell)
	plays vital roles in neuronal differentiation
	DYRK1A and REST are closely related in neurodevelopment
	REST function is required for the differentiation of OPCs (oligodendrocyte precursor cells) into oligodendrocytes, and by regulating the expression of neuronal genes, REST may also regulate the phenotypic plasticity of OPCs
	transcription regulatory mechanism of REST by IFT57 may contribute to the deregulation of transcription observed in the cell model of Huntington disease
	regulates radial migration and the timing of neural progenitor differentiation during neocortical development
	regulates the radial migration coupled to neuronal differentiation, at least in part, by regulating the timing of DCX gene expression during neurogenesis
	sustained presence of REST during neurogenesis interferes with migration and, therefore, with the timing of neuronal differentiation
	central role for REST during neural development in promoting neural stem/progenitor (NS/P) cells self-renewal while restricting the generation and maturation of neurons and oligodendrocytes
	role of REST in the various steps of the expression and function of the dense-core vesicle membrane is critical during development and participates in the dynamic regulation of mature cell physiology
	crucial regulatory function in the heart and its importance for maintaining normal cardiac integrity
	REST/NRSF is a critical factor linking neuronal activity to the activation of intrinsic homeostasis and restoring a physiological level of activity in the entire neuronal network
	during normal ageing, REST is induced in part by cell non-autonomous Wnt signalling
	transcriptional regulator that function as a hub that coordinately regulates multiple aspects of neurogenesis, orchestrates neural differentiation, and preserves the unique neural phenotype
	acts as a flexible and complicated regulator in nervous system, from transcriptional repressor to activator or modulator, and plays a part in neuronal survival or neuronal death
	transcriptional repressor of neuronal genes that has been implicated in development and cancer
	REST and TSPYL2 are regulators of TGFB1 signaling and cell-cycle arrest induced by TGFB1 requires both REST and TSPYL2

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a master repressor of neuronal gene expression and neuronal programmes in non-neuronal lineages

a component	complexing with TFAP4 (repressor complex distinct from REST/NRSF to negatively regulate the expression of target genes in nonneuronal cells and may contribute to suppressing the precocious expression of target genes in fetal brain)
	REST, DCTN1, HTT, HAP1, and RILP form a complex involved in the translocation of REST into the nucleus and HAP1 controls REST cellular localization in neurons

INTERACTION

DNA	binding to the neuron-restrictive silencer element

RNA

small molecule	metal binding,
	Zn2+

protein	Huntingtin
	histone methylase G9a to silence NRSF target genes in nonneuronal cells
	repressor element 1 (RE-1)-silencing transcription factor
	HDAC4 and 5
	JmjC domain-containing protein SMCX, JARID1C/SMCX
	YY1 (YY1 directly regulates expression of the REST gene)
	beta-TRCP binds and ubiquitinates REST and controls its stability through a conserved phospho-degron
	CDYL is a REST corepressor that physically bridges REST and the histone methylase EHMT2 to repress transcription
	DYRK1A (the DYRK1A/REST-SWI/SNF chromatin remodelling complex deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome)
	interacting with BDNF
	PHF21A mediate REST repression
	REST can activate DYRK1A transcription via a neuron-restrictive silencer element at bp &
	8722;833 to &
	8722;815 of the promoter
	interacts with Cbx proteins (CBX2) and regulates polycomb repressive complex 1 occupancy at RE1 elements
	NEUROD2 inhibits REST indirectly by involving the inhibitor of myogenic genes, ZEB1, which binds response elements in REST 5prime-UTR
	new transcriptional target of IFT57 (could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells)
	TERF2 binds and stabilizes REST, thereby enforcing neuronal gene silencing
	DCX is a direct REST target gene containing a canonical RE1 site and REST binds to this site efficiently at the NS/P stage
	PPARG may be an important TBX20 co-factor activating energy metabolism genes in the adult heart while REST, a known transcriptional repressor, may act with TBX20 to silence genes controlling genetic programs unrelated to adult heart function
	REST promoted primordial germ cells (PGCs) survival via regulation of the MAP2K5 expression
	SP1 is a fundamental activator of basal SYN1 gene expression, whose activity is modulated by the neural master regulator REST and CpG methylation
	strict functional interplay between SP1 and REST, which exerts a dominant negative role on SP1 function and chromatin affinity on the SYN1 promoter
	REST represses PDYN expression in neuroblastoma cells and the adult human brain and may have implications for mental health and brain/mental disorders
	ZFP36L2, associated previously only with female fertility and hematopoiesis, regulates REST mRNA stability
	mechanistically, SRCAP recruits the transcriptional regulator REST to the PRDM16 promoter and induces expression of this transcription factor

cell & other

REGULATION

inhibited by	DYRK1A (deregulation of REST is a very early pathological consequence of trisomy 21 with potential to disturb the development of all embryonic lineages)
	NEUROD2

repressed by	SMARCA4 (facilitates REST repression by increasing the interaction between REST and chromatin)
		CoREST

ASSOCIATED DISORDERS

corresponding disease(s)

GINGF5

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral         abnormal expression in cerebellum-specific tumors by blocking neuronal differentiation tumoral   deletion     frequent target of deletion in colorectal cancer constitutional     --low   reduced expression in trisomy 21 from undifferentiated embryonic stem (ES) cells to adult brain constitutional     --over   reduced the level of transcriptional activation through the N- and C-terminals, suggesting the recruitment of a histone deacetylase constitutional     --low   required for the differentiation of pluripotent cells into lineage-restricted neuronal progenitors during neurogenesis in the dentate gyrus of the hippocampus constitutional     --over   in Huntington disease, an excess of REST accumulates in the nucleus because of a mutation of the -huntingtin protein, which might repress the activity-dependent transcription of BDNF-PI, resulting in a loss of neuronal traits and the degeneration of neurons tumoral         REST–less tumors represent a distinct, aggressive subset of breast tumors constitutional       loss of function causes aberrant expression of RGC (retinal ganglion cell) transcription factors in proliferating RPCs (retinal progenitor cell), independent of ATOH7, resulting in increased RGC formation ( constitutional     --over   suppress KCNQ2 expression, and upregulated in response to neuropathic injury identifying the likely mechanism of KCNQ2 regulation tumoral     --low   expression significantly lower in breast cancer samples compared to normal and benign breast samples constitutional     --low   , in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins

Susceptibility

Variant & Polymorphism

Candidate gene	for contribution to Down syndrome pathology through DYRK1A-mediated deregulation
Marker
Therapy target
	System Type Disorder Pubmed miscelleaneous pain   peripheral targets for the treatment of neuropathic pain neurology neurodegenerative huntington chorea may be an important target for neurodegenerative diseases like Huntington disease, is also involved in the regulation of a broad range of additional cellular pathways

ANIMAL & CELL MODELS