Transcription factor 7-like 2 (TCF7l2) regulates CNS myelination separating from its role in upstream oligodendrocyte differentiation.

Oligodendrocyte progenitor cells (OPCs) differentiation into oligodendrocytes (OLs) and subsequent myelination are two closely coordinated yet differentially regulated steps for myelin formation and repair in the CNS. Previously thought as an inhibitory factor by activating Wnt/beta-catenin signaling, we and others have demonstrated that the Transcription factor 7-like 2 (TCF7l2) promotes OL differentiation independent of Wnt/beta-catenin signaling activation. However, it remains elusive if TCF7l2 directly controls CNS myelination separating from its role in upstream oligodendrocyte differentiation. This is partially because of the lack of genetic animal models that could tease out CNS myelination from upstream OL differentiation. Here, we report that constitutively depleting TCF7l2 transiently inhibited oligodendrocyte differentiation during early postnatal development, but it impaired CNS myelination in the long term in adult mice. Using time-conditional and developmental-stage-specific genetic approaches, we further showed that depleting TCF7l2 in already differentiated OLs did not impact myelin protein gene expression nor oligodendroglial populations, instead, it perturbed CNS myelination in the adult. Therefore, our data convincingly demonstrate the crucial role of TCF7l2 in regulating CNS myelination independent of its role in upstream oligodendrocyte differentiation.

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.

Transcription factor 7 like 2 promotes metastasis in hepatocellular carcinoma via NEDD9-mediated activation of AKT/mTOR signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system, and the exact mechanism of HCC is still unclear. Transcription factor 7 like 2 (TCF7L2) plays a pivotal role in cell proliferation and stemness maintenance. However, the exact mechanism of TCF7L2 in HCC remains unclear. METHODS: Clinical samples and public databases were used to analyze the expression and prognosis of TCF7L2 in HCC. The function of TCF7L2 in HCC was studied in vitro and in vivo. ChIP and luciferase assays were used to explore the molecular mechanism of TCF7L2. The relationship between TCF7L2 and NEDD9 was verified in HCC clinical samples by tissue microarrays. RESULTS: The expression of TCF7L2 was upregulated in HCC, and high expression of TCF7L2 was associated with poor prognosis of HCC patients. Overexpression of TCF7L2 promoted the metastasis of HCC in vitro and in vivo, while Knockdown of TCF7L2 showed the opposite effect. Mechanically, TCF7L2 activated neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) transcription by binding to the -1522/-1509 site of the NEDD9 promoter region, thereby increasing the phosphorylation levels of AKT and mTOR. The combination of TCF7L2 and NEDD9 could distinguish the survival of HCC patients. CONCLUSIONS: This study demonstrated that TCF7L2 promotes HCC metastasis by activating AKT/mTOR pathway in a NEDD9-dependent manner, suggesting that potential of TCF7L2 and NEDD9 as prognostic markers and therapeutic targets for HCC.

PAX1 represses canonical Wnt signaling pathway and plays dual roles during endoderm differentiation.

BACKGROUND: Paired box 1 (PAX1) is a transcription factor and essential for the development of pharyngeal pouches-derived tissues, including thymus. PAX1 mutations are identified in Severe Combined Immunodeficiency (SCID) patients with Otofaciocervical Syndrome Type 2 (OTFCS2). However, despite the critical roles of PAX1 in embryonic development and diseases, detailed insights into its molecular mode of action are critically missing. METHODS: The repressing roles of PAX1 and SCID associated mutants on Wnt signaling pathway were investigated by luciferase reporter assays, qRT-PCR and in situ hybridization in HEK293FT, HCT116 cells and zebrafish embryos, respectively. Co-immunoprecipitation (co-IP) and western blotting assays were carried out to identify the molecular mechanisms underlying PAX1's role on Wnt signaling pathway. hESC based endoderm differentiation, flow cytometry, high-throughput sequencing data analysis, and qRT-PCR assays were utilized to determine the roles of PAX1 during endoderm differentiation. RESULTS: Here, we show that PAX1 represses canonical Wnt signaling pathway in vertebrate cells. Mechanically, PAX1 competes with SUMO E3 ligase PIASy to bind to TCF7L2, thus perturbing TCF7L2 SUMOylation level, further reducing its transcriptional activity and protein stability. Moreover, we reveal that PAX1 plays dual roles in hESC-derived definitive and foregut/pharyngeal endoderm cells, which give rise to the thymus epithelium, by inhibiting Wnt signaling. Importantly, our data show PAX1 mutations found in SCID patients significantly compromise the suppressing ability of PAX1 on Wnt signaling. CONCLUSIONS: Our study presents a novel molecular mode of action of PAX1 in regulation of canonical Wnt signaling and endoderm differentiation, thus providing insights for the molecular basis of PAX1 associated SCID, offering better understanding of the behavior of PAX1 in embryogenesis.

Correlation between TCF7L2 and CAPN10 gene polymorphisms and gestational diabetes mellitus in different geographical regions: a meta-analysis.

BACKGROUND: The association between TCF7L2 and CAPN10 gene polymorphisms and gestational diabetes mellitus (GDM) has been explored in diverse populations across different geographical regions. Yet, most of these studies have been confined to a limited number of loci, resulting in inconsistent findings. In this study, we conducted a comprehensive review of published literature to identify studies examining the relationship between TCF7L2 and CAPN10 gene polymorphisms and the incidence of GDM in various populations. We specifically focused on five loci that were extensively reported in a large number of publications and performed a meta-analysis. METHODS: We prioritized the selection of SNPs with well-documented correlations established in existing literature on GDM. We searched eight Chinese and English databases: Cochrane, Elton B. Stephens. Company (EBSCO), Embase, Scopus, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, and China Science and Technology Journal Database and retrieved all relevant articles published between the inception of the database and July 2022. The Newcastle Ottawa Scale (NOS) was used to evaluate the selected articles, and the odds ratio (OR) was used as the combined effect size index to determine the association between genotypes, alleles, and GDM using different genetic models. Heterogeneity between the studies was quantified and the I2 value calculated. Due to large heterogeneities between different ethnic groups, subgroup analysis was used to explore the correlation between genetic polymorphisms and the incidence of GDM in the different populations. The stability of the results was assessed using sensitivity analysis. Begg's and Egger's tests were used to assess publication bias. RESULTS: A total of 39 articles reporting data on 8,795 cases and 16,290 controls were included in the analysis. The frequency of the rs7901695 genotype was statistically significant between cases and controls in the European population (OR = 0.72, 95% CI: 0.65-0.86) and the American population (OR = 0.61, 95% CI: 0.48-0.77). The frequencies of rs12255372, rs7901695, rs290487, and rs2975760 alleles were also considerably different between the cases and controls in the populations analyzed. CONCLUSIONS: rs7903146, rs12255372, rs7901695, rs290487, and rs2975760 were associated with the incidence of GDM in different populations.

TCF7L2 Polymorphism rs7903146 (C/T) and Gestational Diabetes Influence on Obstetric Outcome: A Romanian Case-Control Study.

Gestational diabetes mellitus (GDM) is one of the most frequent predictors of obstetric outcome among Romanian pregnant women. Thus, we aimed to investigate the role of rs7903146 (C/T) TCF7L2 gene polymorphism in the presence of GDM and to evaluate the influence on maternal-fetal outcomes in a cohort of pregnant women from Northern Transylvania. Our prospective case-control study was performed in a tertiary maternity center on 61 patients diagnosed with GDM and 55 normal pregnant patients. The patients were genotyped for rs7903146 (C/T) polymorphism of the TCF7L2 gene using the PCR-RFLP method between 24 and 28 weeks of gestation. The minor T allele was associated with a high risk of developing GDM (OR 1.71 [95% CI 0.82-3.59]) if both heterozygote and homozygote types were considered. Also, a higher risk of developing GDM was observed in homozygous carriers (OR 3.26 [95% CI 1.10-9.68]). Women with the TT genotype were more likely to require insulin therapy during pregnancy than other genotypes with a 5.67-fold increased risk ([1.61-19.97], p = 0.015). TT homozygote type was significantly associated with fetal macrosomia for birth weights greater than the 95th percentile (p = 0.034). The homozygous TT genotype is associated with an increased risk of developing GDM. Also, rs7903146 (C/T) TCF7L2 variant is accompanied by a high probability of developing insulin-dependent gestational diabetes mellitus (ID-GDM). The presence of at least one minor T allele was associated with a higher risk of fetal macrosomia.

TCF7L2 and FTO Polymorphisms Are Associated with Type 2 Diabetes Mellitus Risk in Kuwait.

OBJECTIVE: Despite the high prevalence of type 2 diabetes mellitus (T2DM) and obesity in the region, reports are limited on genetic risk factors associated with T2DM risk in Kuwait. Our aim was to investigate the association of reported FTO and TCF7L2 T2DM genetic risk variants in Kuwaiti T2DM patients. SUBJECTS AND METHODS: FTO rs9939609 and TCF7L2 rs7903146 variants were genotyped in 203 T2DM patients and 162 healthy controls. Data analysis included Fisher's exact test, χ2 test, and linear and logistic regression analyses. RESULTS: FTO rs9939609 (AA) and TCF7L2 rs7903146 (TT) genotypes associated with T2DM risk among Kuwaitis (p = 0.0016 and p < 0.0001; respectively). Both variants had the strongest association with T2DM risk in an autosomal recessive inheritance model (FTO rs9939609A: odds ratio (OR) 2.136, 95% confidence interval (CI): 1.21-3.67, p = 0.0075; TCF7L2 rs7903146T: OR 3.283, 95% CI: 1.92-5.76, p < 0.0001). Moreover, rs7903146T associated with risk of peripheral neuropathy (ß = 0.735, 95% CI: 0.514-0.96, p < 0.001) and risk of myocardial infarction (ß = 0.36, 95% CI: 0.024-0.7, p = 0.036) in T2DM patients. CONCLUSION: The increased susceptibility of Kuwaitis to T2DM is influenced by the same common genetic factors found in other T2DM populations. Further investigations of other T2DM genetic risk factors in Kuwait should refine and further support the clinical utility of a genetic risk score in predicting T2DM risk in a high-risk population such as Kuwait.

Treatment and genetic analysis of multiple supernumerary and impacted teeth in an adolescent patient.

BACKGROUND: Multiple supernumerary teeth, combined with numerous impacted teeth, can lead to various malocclusions, posing significant treatment challenges. While certain genes associated with syndromic cases of multiple supernumerary and impacted teeth have been identified, the etiologies of non-syndromic cases still largely remain elusive. CASE PRESENTATION: Here, we report a treatment of a 12-year-old boy who presented with 10 supernumerary teeth and 6 impacted teeth, accompanied by a genetic analysis to explore the underlying etiology. During the treatment, fifteen teeth were extracted, and various skilled techniques, including the closed-eruption technique and the application of by-pass arches, were utilized. Post-treatment, traction was successful for all the impacted teeth, without any tooth mobility or reduction in gingival height. Space closure, well-aligned teeth, and excellent functional occlusion were achieved. Furthermore, comprehensive genetic analysis was conducted through whole-exome sequencing on the patient and his parents, which revealed a potential link between the patient's numerous supernumerary teeth and abnormal mineralization. Notably, the p.Ser496Pro variant in the TCF7L2 gene was identified as a potential candidate variant in this patient. CONCLUSIONS: Overall, our findings not only report the treatment of a rare case involving multiple supernumerary and impacted teeth but also offer valuable insights into the molecular basis of supernumerary teeth.

Association of Polymorphic Variants of TCF7L2 and PPARG Genes with Metabolic Markers in Patients with Early Disorders of Carbohydrate Metabolism.

We performed complex analysis of the association of polymorphic variants rs7903146 of the TCF7L2 gene and rs1801282 of the PPARG gene with metabolic parameters, insulin resistance, and ß-cell function in a group of patients with early signs of carbohydrate metabolism disturbances in a sample of Tyumen citizens. The study group consisted of 64 people (39 women, 25 men) aged 40-70 years. The distribution of frequencies of alleles and genotypes of the polymorphic markers rs7903146 and rs1801282 was analyzed and associations of carriage of major homozygous polymorphisms with various phenotypic traits were identified. Genotyping for polymorphic variants of TCF7L2 and PPARG genes was performed using allele-specific PCR with primers provided by Synthol company. Carriers of homozygotes for allele C of the polymorphic marker rs7903146 significantly differed from other respondents by a higher level of C-peptide, as well as by the presence of associations with waist circumference, elevated level of glycated hemoglobin, and arterial hypertension. Carriers of homozygotes for the allele C of the rs1801282 polymorphism of the PPARG gene differed from the group of carriers of homozygotes for the allele G and the group of heterozygote carriers by higher levels of triglycerides, as well as the presence of associations with waist circumference and the level of glycated hemoglobin.

Association of TCF7L2 Gene Variant (rs12255372) with Polycystic Ovary Syndrome and its Effect Modification of the Disease Phenotype.

Polycystic ovary syndrome (PCOS) and type-2 diabetes mellitus (T2DM) share common genetic features. Transcription factor 7-like-2 (TCF7L2) is consistently studied T2DM susceptibility locus. However, limited studies on TCF7L2 have failed to demonstrate any link with the PCOS risk. Therefore, we investigated the association of TCF7L2 polymorphic variant (rs12255372) with the PCOS risk. We recruited 120 PCOS cases, diagnosed as per Rotterdam 2003 criteria, and an equal number of age-matched controls. Besides a detailed clinical assessment, subjects underwent biochemical and hormonal profiling. Genotyping for rs12255372 was done by PCR-RFLP. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95%CIs) of genotype-phenotype correlations. The PCOS cases reported fewer menstrual cycles per year and exhibited signs of hyperandrogenism. The heterozygous genotype of rs12255372 was strongly associated with the PCOS risk (OR = 2.00; 95%CI: 1.07-3.76). Unlike controls, only 3 cases harbored TT genotype, and the PCOS risk persisted in the dominant model (GT + TT) as well. Moreover, we found a synergistic effect modification by the variant genotype in the subjects who had family histories of T2DM, hirsutism, or menstrual irregularities. We report a significant association of the TCF7L2 polymorphic variant rs12255372 with the PCOS risk.

Milder loss of insulin-containing islets in individuals with type 1 diabetes and type 2 diabetes-associated TCF7L2 genetic variants.

AIMS/HYPOTHESIS: TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme. METHODS: We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African American, 7.3% Hispanic) using data pertaining to residual beta cell number; quantified islets containing insulin-positive beta cells in pancreatic tissue sections; and expressed these values as a percentage of the total number of islets from each donor (mean ± SD ICI% 9.8±21.5, range 0-92.2). RESULTS: Donors with a high ICI% (≥5) (n=30; 27%) vs a low ICI% (<5) (n=80; 73%) were older at onset (15.3±6.9 vs 11.1±8 years, p=0.013), had a shorter diabetes duration at donor tissue procurement (7.0±7.4 vs 18.5±14.3 years, p<0.001), a higher African ancestry score (0.2±0.3 vs 0.1±0.2, p=0.043) and a lower European ancestry score (0.7±0.3 vs 0.9±0.3, p=0.023). After adjustment for age of onset (p=0.105), diabetes duration (p<0.001), BMI z score (p=0.145), sex (p=0.351) and African American race (p=0.053), donors with the TCF7L2 rs7903146 T allele (TC or TT, 45.5%) were 2.93 times (95% CI 1.02, 8.47) more likely to have a high ICI% than those without it (CC) (p=0.047). CONCLUSIONS/INTERPRETATION: Overall, these data support the presence of a type 1 diabetes endotype associated with a genetic factor that predisposes to type 2 diabetes, with donors in this category exhibiting less severe beta cell loss. It is possible that in these individuals the disease pathogenesis may include mechanisms associated with type 2 diabetes and thus this may provide an explanation for the poor response to immunotherapies to prevent type 1 diabetes or its progression in a subset of individuals. If so, strategies that target both type 1 diabetes and type 2 diabetes-associated factors when they are present may increase the success of prevention and treatment in these individuals.

Tcf7l2 in hepatocytes regulates de novo lipogenesis in diet-induced non-alcoholic fatty liver disease in mice.

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development. METHODS: Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2f/f). Alb-Cre;Tcf7l2f/f and their wild-type (Tcf7l2f/f) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology. RESULTS: Alb-Cre;Tcf7l2f/f essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2f/f mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions. CONCLUSIONS/INTERPRETATION: In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL. DATA AVAILABILITY: RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449 ).

TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus.

Neuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but only a few examples of such regulators have been provided in vertebrates. We hypothesised that TCF7L2 regulates different stages of postmitotic differentiation in the thalamus, and functions as a thalamic terminal selector. To investigate this hypothesis, we used complete and conditional knockouts of Tcf7l2 in mice. The connectivity and clustering of neurons were disrupted in the thalamo-habenular region in Tcf7l2-/- embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with a postnatal Tcf7l2 knockout, the induction of genes that confer thalamic terminal electrophysiological features was impaired. Many of these genes proved to be direct targets of TCF7L2. The role of TCF7L2 in terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that control stage-specific genetic programmes and regional subroutines, maintain regional transcriptional network during embryonic development, and induce terminal selection postnatally.

Association of transcription factor 7-like 2 rs12255372 polymorphism with susceptibility of type 2 diabetes mellitus in Bangladeshi population.

Polymorphism of transcription factor 7-like 2 (TCF7L2) has a link with type 2 diabetes mellitus (T2DM) through ß cell dysfunction that causes defect in blood glucose homeostasis. This case-control study recruited 67 T2DM as cases and 65 age-matched healthy individuals as controls to determine whether the polymorphism rs12255372 (G > T) in the TCF7L2 gene have an association with T2DM in Bangladeshi population. Genomic DNA was purified from peripheral whole blood sample and direct Sanger sequencing was done for genotyping of SNP. Bivariate logistic regression was done to find out the association between genetic variant and T2DM. In our study, the minor T allele frequency was significantly more frequent in T2DM group than healthy controls (29.1% vs. 16.9%). After adjusting with confounding factors, heterozygous-genotype GT had higher odds of developing T2DM (OR 2.4; 95% CI: 1.0-5.5; p value = 0.04) and in dominant model, having SNP in TCF7L2 increased the risk of T2DM 2.3 times (95% CI: 1.0-5.2; p value = 0.04). In interaction model, genetic susceptible SNP cases interacted significantly with increasing age and BMI, female gender, and having family history of diabetes mellitus to develop T2DM (pinteraction < 0.001). Having minor T allele either in heterozygous or homozygous variant form of rs12255372 (G > T) TCF7L2 had significant association with T2DM. In conclusion, TCF7L2 gene variant increases risk of developing T2DM among the Bangladeshi population.

TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut-liver crosstalk.

FGF19/FGF15 is an endocrine regulator of hepatic bile salt and lipid metabolism, which has shown promising effects in the treatment of NASH in clinical trials. FGF19/15 is transcribed and released from enterocytes of the small intestine into enterohepatic circulation in response to bile-induced FXR activation. Previously, the TSS of FGF19 was identified to bind Wnt-regulated TCF7L2/encoded transcription factor TCF4 in colorectal cancer cells. Impaired Wnt signaling and specifical loss of function of its coreceptor LRP6 have been associated with NASH. We, therefore, examined if TCF7L2/TCF4 upregulates Fgf19 in the small intestine and restrains NASH through gut-liver crosstalk. We examined the mice globally overexpressing, haploinsufficient, and conditional knockout models of TCF7L2 in the intestinal epithelium. The TCF7L2+/- mice exhibited increased plasma bile salts and lipids and developed diet-induced fatty liver disease while mice globally overexpressing TCF7L2 were protected against these traits. Comprehensive in vivo analysis revealed that TCF7L2 transcriptionally upregulates FGF15 in the gut, leading to reduced bile synthesis and diminished intestinal lipid uptake. Accordingly, VilinCreert2 ; Tcf7L2fl/fl mice showed reduced Fgf19 in the ileum, and increased plasma bile. The global overexpression of TCF7L2 in mice with metabolic syndrome-linked LRP6R611C substitution rescued the fatty liver and fibrosis in the latter. Strikingly, the hepatic levels of TCF4 were reduced and CYP7a1 was increased in human NASH, indicating the relevance of TCF4-dependent regulation of bile synthesis to human disease. These studies identify the critical role of TCF4 as an upstream regulator of the FGF15-mediated gut-liver crosstalk that maintains bile and liver triglyceride homeostasis.

Association between TCF7L2 polymorphism and type 2 diabetes mellitus susceptibility: a case-control study among the Bangladeshi population.

BACKGROUND: Diabetes is a severe health burden for Bangladesh. Genetic polymorphism has been reported to be one of the major risk factors for diabetes in various studies. TCF7L2 (transcription factor 7 like 2) transcripts in the human ß-cell have effects on ß-cell survival, function, and Wnt signaling activation. This study aimed to evaluate the frequency and association of various polymorphisms namely TCF7L2 rs12255372 and rs7903146 among Bangladeshi patients with T2DM (Type 2 Diabetes Mellitus). METHODS: This case-control study included 300 patients with T2DM and 234 healthy individuals from two health facilities in the Chattogram Division of Bangladesh. Anthropometric measurements were assessed using a self-reported, structured, eight-item questionnaire. The polymorphisms were identified by PCR-RFLP and sequencing method. RESULTS: A strong association of T2DM with polymorphisms was observed, including rs12255372 (p = 0.0004) and rs7903146 (p = 0.005). It was observed that the risk genotype at rs12255372 was associated with age (p = 0.009), a family history of diabetes (p < 0.0001), and HbA1C (p < 0.0001). Furthermore, it was found that rs12255372 was substantially associated with hypertension (p = 0.03), eye problems (p = 0.01), and neurological abnormalities (p = 0.02). CONCLUSION: This study postulates that TCF7L2 genetic polymorphism is associated with the risk of T2DM among the studied Bangladeshi population. The findings should be replicated through more studies with a large number of samples and in different populations.

Genomic profile of diabetic retinopathy in a north indian cohort.

BACKGROUND: Diabetic Retinopathy (DR) is one of the major microvascular complications of diabetes. Being a complex disease, it is important to delineate the genetic and environmental factors that influence the susceptibility to DR in a population. Therefore, the present study was designed to investigate the role of genetic and lifestyle risk factors associated with DR susceptibility in a North-Indian population. METHODS: A total of 848 subjects were enrolled, comprising of DR cases (n = 414) and healthy controls (n = 434). The Sequenom MassARRAY technology was used to perform target genome analysis of 111 SNPs across 57 candidate genes and 14 intergenic region SNPs that are involved in the metabolic pathways associated with type 2 diabetes (T2D) and DR. Allele, genotype and haplotype frequencies were determined and compared among cases and controls. Logistic regression models were used to determine genotype-phenotype and phenotype-phenotype correlations. RESULTS: The strongest association was observed with TCF7L2 rs12255372 T allele [p < 0.0001; odds ratio (OR) = 1.81 (1.44-2.27)] and rs11196205 C allele [p < 0.0008; OR = 1.62 (1.32-1.99)]. Genotype-phenotype and phenotype-phenotype correlations were found in the present study. CONCLUSION: Our study provides strong evidence of association between the TCF7L2 variants and DR susceptibility.

Identification of DNA methylation change in TCF7L2 gene in the blood of type 2 diabetes mellitus as a predictive biomarker in Iraq Kurdistan region by using methylation-specific PCR.

Objective. Nowadays, type 2 diabetes mellitus (T2D) is the most common chronic endocrine disorder affecting an estimated 5-10% of adults worldwide, and this disease also rapidly increased among the population in the Kurdistan region. This research aims to identify DNA methylation change in the TCF7L2 gene as a possible predictive T2D biomarker. Methods. One hundred and thirteen participants were divided into three groups: diabetic (47), prediabetic (36), and control (30). The study was carried out in patients who visited the private clinical sector between August and December 2021 in Koya city (Iraq Kurdistan region) to determine DNA methylation status using a methylation-specific PCR (MSP) with paired primers for each methylated and non-methylated region. In addition, the X2 Kruskal-Wallis statistical and Wilcoxon signed-rank tests were used, p<0.05 was considered significant. Results. The results showed hypermethylation of DNA in the promoter region in diabetic and prediabetic groups compared to the healthy controls. Different factors affected the DNA methylation level, including body max index, alcohol consumption, family history, and physical activity with the positive Coronavirus. Conclusion. The results obtained indicate that DNA methylation changes in the TCF7L2 promoter region may be used as a potential predictive biomarker of the T2D diagnosis. However, the findings obtained in this study should be supported by additional data.

The Wnt Effector TCF7l2 Promotes Oligodendroglial Differentiation by Repressing Autocrine BMP4-Mediated Signaling.

Promoting oligodendrocyte (OL) differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector transcription factor 7-like 2 (TCF7l2) was upregulated in MS lesions and had been proposed to inhibit OL differentiation. Recent data suggest the opposite yet underlying mechanisms remain elusive. Here, we unravel a previously unappreciated function of TCF7l2 in controlling autocrine bone morphogenetic protein (BMP)4-mediated signaling. Disrupting TCF7l2 in mice of both sexes results in oligodendroglial-specific BMP4 upregulation and canonical BMP4 signaling activation in vivo Mechanistically, TCF7l2 binds to Bmp4 gene regulatory element and directly represses its transcriptional activity. Functionally, enforced TCF7l2 expression promotes OL differentiation by reducing autocrine BMP4 secretion and dampening BMP4 signaling. Importantly, compound genetic disruption demonstrates that oligodendroglial-specific BMP4 deletion rescues arrested OL differentiation elicited by TCF7l2 disruption in vivo Collectively, our study reveals a novel connection between TCF7l2 and BMP4 in oligodendroglial lineage and provides new insights into augmenting TCF7l2 for promoting remyelination in demyelinating disorders such as MS.SIGNIFICANCE STATEMENT Incomplete or failed myelin repairs, primarily resulting from the arrested differentiation of myelin-forming oligodendrocytes (OLs) from oligodendroglial progenitor cells, is one of the major reasons for neurologic progression in people affected by multiple sclerosis (MS). Using in vitro culture systems and in vivo animal models, this study unraveled a previously unrecognized autocrine regulation of bone morphogenetic protein (BMP)4-mediated signaling by the Wnt effector transcription factor 7-like 2 (TCF7l2). We showed for the first time that TCF7l2 promotes oligodendroglial differentiation by repressing BMP4-mediated activity, which is dysregulated in MS lesions. Our study suggests that elevating TCF7l2 expression may be possible in overcoming arrested oligodendroglial differentiation as observed in MS patients.

The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes.

The TCF7L2 protein is a key transcriptional effector of the Wnt/ß-catenin signaling pathway, regulating gene expression. It was initially identified in cancer research and embryologic developmental studies. Later, the TCF7L2 gene was linked to type 2 diabetes (T2D), implicating TCF7L2 and Wnt-signaling in metabolic disorders and homeostasis. In fact, TCF7L2-T2D variants confer the greatest relative risk for T2D, unquestionably predicting conversion to T2D in individuals with impaired glucose tolerance. We aim to describe the relevance of TCF7L2 in other human disorders. The TCF7L2-single nucleotide polymorphisms (SNPs) and T2D-risk association have been replicated in numerous follow-up studies, and research has now been performed in several other diseases. In this article, we discuss common TCF7L2-T2D variants within the framework of their association with human diseases. The TCF7L2 functional regions need to be further investigated because the molecular and cellular mechanisms through which TCF7L2 contributes to risk associations with different diseases are still not fully elucidated. In this review, we show the association of common TCF7L2-T2D variants with many types of diseases. However, the role of rare genetic variations in the TCF7L2 gene in distinct diseases and ethnic groups has not been explored, and understanding their impact on specific phenotypes will be of clinical relevance. This offers an excellent opportunity to gain a clearer picture of the role that the TCF7L2 gene plays in the pathophysiology of human diseases. The potential pleiotropic role of TCF7L2 may underlie a possible pathway for comorbidity in human disorders.