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FLASH GENE

Symbol

TCF4

contributors: mct/shn - updated : 31-01-2016

HGNC name	transcription factor 4
HGNC id	11634

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	DEL18QD chromosome 18q distal deletion FECD3 Fuchs endothelial corneal dystrophy 3 PTHS Pitt-Hopkins syndrome
Location	18q21.2      Physical location : 52.889.561 - 53.255.860
Synonym name	SL3-3 enhancer factor 2
	immunoglobulin transcription factor 2
	immunoglobulin transcription factor-2B
	class B basic helix-loop-helix protein 19
Synonym symbol(s)	SEF2, ITF-2B, ITF2, SEF2.1, E2-2, MGC149723, MGC149724, SEF2-1B, bHLHb19, PTHS, SEF-2, SEF2-1, SEF2-1A, TCF-4

DNA

TYPE	cluster
STRUCTURE	367.48 kb     21 Exon(s)

10 Kb 5' upstream gene genomic sequence study

motif	repetitive sequence   triplet
text structure	expanding intronic CTG repeat, highly polymorphic flanked by a stable CTC repeat and a GA rich region in the same intron

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	cen - D18S34 - TCF4 - D18S69 - D18S41 - D18S64 - qter

RNA

TRANSCRIPTS	type	messenger

text

Alternative splicing of TCF4 gene allows the production of + or & 8722; and full-length or delta protein isoforms that include or lack a four amino acid insertion and the NLS-containing region, respectively diversity of isoforms is increased by alternative splicing of several internal exons (PMID: 21789225)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003199 (transcript variant 2) 20 splicing 8320 NP_003190 - 667 - 2009 19635457 NM_001083962 (transcript variant 1) 20 splicing 8332 NP_001077431 71.7 671 - 2009 19635457 also known as SERF21A, ITF2A lacks N-terminal sequences found in ITF2B expression is frequently lost in colorectal cancers, suggesting that loss of ITF-2A provides cancer cells with a growth advantage NM_001243227 (transcript variant 4) 18 splicing 8166 NP_001230156 - 647 - 2009 19635457 NM_001243232 (transcript variant 8) 16 splicing 7788 NP_001230161 - 600 - 2009 19635457 NM_001243231 (transcript variant 7) 17 splicing 7754 NP_001230160 - 625 - 2009 19635457 NM_001243230 (transcript variant 6) 19 splicing 7793 NP_001230159 - 664 - 2009 19635457 NM_001243228 (transcript variant 5) 18 splicing 8276 NP_001230157 - 677 - 2009 19635457 NM_001243236 (transcript variant 12) 13 splicing 7365 NP_001230165 - 507 - 2009 19635457 NM_001243235 (transcript variant 11) 13 splicing 7349 NP_001230164 - 507 - 2009 19635457 NM_001243234 (transcript variant 10) 13 splicing 7361 NP_001230163 - 511 - 2009 19635457 NM_001243226 (transcript variant 3) 21 splicing 8086 NP_001230155 - 773 - 2009 19635457 NM_001243233 (transcript variant 9) 16 splicing 7717 NP_001230162 - 537 - 2009 19635457

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart         Digestive pharynx       highly Nervous brain       highly Homo sapiens Respiratory lung

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow     highly Connective adipose     highly Connective bone       Muscular striatum skeletal

cell lineage	preB cells
cell lines	neuroblastoma cells (
fluid/secretion	blood

at STAGE

physiological period

embryo, pregnancy

Text	heart, brain, placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a basic helix-loop-helix (HLH) DNA binding domain
	two binding domains for C terminal binding protein
	both TCF4 activation domains are able to activate transcription independently, but act synergistically in combination
	C-terminal bHLH domain that mediates dimerization and DNA binding, and the transcriptional activation domain 2

mono polymer

homomer , heteromer , dimer , trimer

HOMOLOGY

interspecies	ortholog to Tcf4, Rattus Norvegicus
	ortholog to Tcf4, mus musculus
	ortholog to tcf4, Danio rerio

Homologene

FAMILY

basic helix-loop-helix (BHLH) family of transcription factors

CATEGORY

transcription factor , tumor suppressor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	playing a role in regulation of melanogenesis through melanocyte differentation and regulation of melanogenic genes
	regulating intestinal tumorigenesis by interaction with c-Jun (by integrating JNK and APC/beta-catenin, two distinct pathways activated by WNT signaling)
	playing an important role in neural development and differentiation
	playing a prominent role in the regulation of differentiation processes
	key transcription factor, with TCF3, that collaborate with beta-catenin in its established role in hair follicle stem cell activation
	with TCF3 may be essential for establishing and maintaining all skin epithelial stem cells through Wnt-dependent and Wnt-independent roles
	regulates a number of convergent signaling pathways involved in cell differentiation and survival in addition to a subset of clinically important mental retardation genes
	a dynamic interplay of TCF3,TCF4 transcription factors governs MYC gene expression in colo-rectal cancer
	TCF3 together with TCF4 controlled germinal center (GC) B cell and plasma cell development
	TCF3, TCF4 are central regulators of B cell immunity

CELLULAR PROCESS	cell life, differentiation
	nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

text	transcriptional activator

PATHWAY

metabolism

signaling

signal transduction

Wnt signaling pathway

a component	forming homodimers or heterodimers with myogenin
	forming a ternary complex with JUN, CTNNB1 (beta-cetanin)
	heterodimerize with several bHLH transcription factors that play important roles in the development of the nervous system, ATOH1, ASCL1, NEUROD1 and NEUROD2

INTERACTION

DNA	binding to the E box in the promoter SSTR2 (
	preferentially binding to either 5'- ACANNTGT-3' or 5'-CCANNTGG-3'

RNA

small molecule

protein	myogenic differentiation 1, MyoD1 (
	Id1, Id2, and Id3 (
	fibroblast growth factor (FGF)-1 promoter, FGF-1.B (
	calmodulin (
	HASH1 (
	Id4 (
	beta-catenin, CTNNB (
	Math1 (
	menin (
	CDX2
	FGFR3
	ZEB1 is an effector of CTNNB1/TCF4 signaling in epithelial-to-mesenchymal transition and tumor progression
	FAM96B is an interaction partner of TCF4
	binds to E-box DNA sequences (CANNTG)
	SOX9 regulates LRP6, TCF4 expression and WNT/CTNNB1 activation in breast cancer
	AGBL1 interacts biochemically with the FCD (Fuchs corneal dystrophy) -associated protein TCF4 and the mutations found in our cohort of FCD individuals diminish this interaction
	PLAGL1 interacts with TCF4, and PLAGL1 and TCF4 expression concomitantly increased during neuronal progenitor differentiation
	WNT1 regulates the expression of CD36 through TCF4 and PPARG
	suppresses angiogenesis after ischemic injury and impairs Wnt/CTNNB1 signaling by disrupting the interaction between CTNNB1 and TCF4
	SPINDOC associates with TCF4 in a SPIN1-dependent manner and dampens SPIN1 coactivator activity
	ZNF433 enhanced the binding between CTNNB1 and TCF4
	KIFC1, activated by TCF4, functions as an oncogene and promotes HCC pathogenesis through regulating HMGA1 transcriptional activity

cell & other

Ephrussi box-like motif within the glucocorticoid response element in the enhancer of the murine leukemia virus SL3-3 (

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

PTHS , DEL18QD , FECD3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional         bipolar disorder

Susceptibility

to schizophrenia to autism to Fuchs' corneal dystrophy (

Variant & Polymorphism SNP , repeat	very enlarged CTG alleles maybe associated to bipolar disorder
	a marker in intron 4 specifically associated to schizophrenia
	region of hemizygosity including TCF4, NETO1, and FBXO15 significantly more likely to exhibit autistic-like behaviors
	rs17089887 and rs17089925 strongly associated with Fuchs' corneal dystrophy (
	association of TCF4 (rs613872, rs9954153, rs2286812 )wih Fuchs' corneal dystrophy

Candidate gene	for severe mental retardation in del18q
Marker
Therapy target
	System Type Disorder Pubmed neurosensorial visual anterior chamber targeted (CAG)7 ASO (antisense oligonucleotide) treatment reduces gain-of-function RNA toxicity induced by TCF4 CTG18.1 expansion, in a cellular and human genomic context

ANIMAL & CELL MODELS

	Tcf4(-/-) mice have disrupted pontine nucleus development (
	Tcf3/4-null primary mouse keratinocyte cultures show a growth defect, with inability to maintain long-term epidermal homeostasis (Nguyen 2009)