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FLASH GENE

Symbol

TCF7L2

contributors: mct/pgu - updated : 27-12-2018

HGNC name	transcription factor 7-like 2 (T-cell specific, HMG-box)
HGNC id	11641

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

text

complex alternative splicing pattern producing theoretically at least 256 forms, with five alternative exons 4, 13, 14, 15, 16 and an alternative use of three consecutive 3' exons changes the reading frame in the last exon (17) leading to the synthesis of a number of isoforms with short, medium or long-size C terminal ends expression of TCF7L2 alternative exons represents a tissue-specific signature; a unique splicing form of TCF7L2 is expressed in pancreatic islets, pancreas and colon but not in other tissues examined here; expression of this splicing form correlates with expression of proinsulin in glucose-stimulated pancreatic islets; expression of alternatively spliced forms of TCF7L2 in eight human tissues examined here is not associated with T2D-associated risk variants (PMID: 19602480)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001146283 13 - 4021 NP_001139755 - 489 - 2000 10919662 long Cter NM_001146274 14 - 4022 NP_001139746 - 602 - 2000 10919662 long C ter NM_030756 14 - 4004 NP_110383 - 596 - 2000 10919662 TCF4E medium C ter use alternative transcription start site TSS1, located at 536 bp from the first translation start site acetylated at lysine K& 8321;&8325;&8320; by CREBBP NM_001146284 13 - 3919 NP_001139756 - 455 - 2000 10919662 long C ter NM_001198530 11 - 3778 NP_001185459 - 408 - 2012 23086040 short TCF7L2 mRNA variant in subcutaneous fat regulated by weight loss and associated with hyperglycemia and impaired insulin action in adipose tissue NM_001146285 13 - 3953 NP_001139757 63.47 579 - 2000 10919662 TCF4J TCF-4J and TCF-4K differed by only five amino acids (the SxxSS motif) its expression produced striking features of malignant transformation characterized by high cell proliferation rate, migration and colony formation even though its transcriptional activity was low NM_001198531 13 - 3949 NP_001185460 51.79 465 - 2000 10919662 TCF4G NM_001198525 15 - 4092 NP_001185454 - 476 - 2000 10919662 TCF4I NM_001198528 15 - 4029 NP_001185457 - 459 - 2000 10919662 NM_001198529 13 - 3931 NP_001185458 - 459 - 2000 10919662 NM_001198526 13 - 3953 NP_001185455 - 579 - 2000 10919662 TCF4K TCF-4J and TCF-4K differed by only five amino acids (the SxxSS motif) displayed low TCF transcriptional activity; cell proliferation rate and colony formation were reduced as well NM_001146286 12 - 3880 NP_001139758 49.17 442 - 2000 10919662 TCF4B NM_001198527 15 - 4017 NP_001185456 - 455 - 2000 10919662

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 Endocrine parathyroid       highly Reproductive female system breast mammary gland   highly Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a CTNNB binding domain
	a HMG box DNA-binding domain
	two CtBP binding motifs only present in the long size C terminal isoforms

HOMOLOGY

Homologene

FAMILY

TCF/LEF family

CATEGORY

regulatory , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,nucleoplasm,nuclear bodies,PML
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	segment polarity protein, acting as a transcriptional activator
	high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis
	may play a role in both glucose homeostasis and adipogenesis (have an inhibitory role of adipogenesis)
	controls insulin gene expression and insulin secretion in mature pancreatic beta-cells
	may be having pleiotropic tissue-specific roles and alterations in one or more of these functions could lead to T2 Diabetes
	plays a key role in TGFB-mediated activation of the PMEPA1 gene
	important transcription factor in WNT pathway, playing critical roles in oligodendrocyte development
	key role for TCF7L2 in myelination/remyelination processes via a tightly controlled activation of WNT/CTNNB1 pathway and the interaction with OLIG2
	likely a crucial role of TCF7L2 in hepatic glucose metabolism
	TCF7L2 directly activates metabolic genes
	WNT/TCF7L2-dependent signaling could play a role in extravillous trophoblasts (EVTs) differentiation promoting motility and expression of promigratory genes
	is a master regulator of insulin production and processing
	is essential for lateralized fate selection by habenular neurons that can differentiate along two alternative pathways, thereby leading to major neural circuit asymmetries
	plays a cell autonomous role in the control of beta cell function and mass, serving as an important regulator of gene expression and islet cell coordination
	plays key roles in glucose metabolism through actions beyond pancreatic beta cells, but with functionally opposing cell-type specific effects on the maintenance of balanced glucose metabolism
	TCF7L2, a CTNNB1 transcriptional partner, is required for oligodendrocyte differentiation

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

Wnt (APC/beta catenin/TCF pathway)

a component

INTERACTION

DNA

RNA

small molecule

protein	MAD2L2-binding protein (interaction abolished the DNA binding ability of TCF7L2)
	AES interacts with T-cell factor 4 (TCF7L2) and downregulates WNT signaling
	tissue-specific differences in the regulation of WWC1 gene expression involve transcription factor TCF7L2 and a complex alternative promoter system
	TCF7L2 transcriptionally regulated 29 genes related to glucose metabolism, including glucose-6-phosphatase
	during oligodendrocyte maturation, TCF7L2 recruits and cooperates with SOX10 to promote myelination
	stage-specific co-regulators ZBTB33 and SOX10 sequentially interact with TCF7L2 to coordinate the switch at the transitions of differentiation initiation and maturation during oligodendrocyte development
	transcriptional co-activator of CTNNB1
	FRMD5 is a novel direct target of the CTNNB/TCF7L2 complex

cell & other

REGULATION

inhibited by

insulin

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral somatic mutation       in gastrointestinal tumor tumoral fusion       with VTI1A in colorectal cancers constitutional     --over   attenuated insulin secretion, consistent with the extra TCF7L2 translocating CTNNB1 from the plasma membrane pool to the nucleus constitutional     --over   may contribute to cartilage degeneration in Osteoarthritis by augmenting NFKB1 signaling constitutional       gain of function is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease constitutional     --over   may result in enhanced apoptosis of vascular smooth muscle cells—a likely mechanism of action of TAA-associated variants in TCF7L2

Susceptibility

to type 2 gestational diabetes with alteration of the birth weight to polycystic ovary syndrome to type 2 diabetes (T2D) to Thoracic aortic aneurysm (TAA)

Variant & Polymorphism SNP	increasing thre risk of type 2 diabetes and altering birth weight
	polymorphisms that may confer an increased risk for early impairment of glucose metabolism in obese children
	rs11196236 and rs11196229 increasing the risk of polycystic ovary syndrome
	rs7903146 and rs12255372, located within introns 3 and 4 of the gene and most strongly associated with T2D
	TCF7L2 rs7903146 polymorphism was associated with susceptibility to gestational diabetes mellitus (GDM)
	variants within the third intron of TCF7L2 significantly associated with TAA

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS