Redundant enhancers and causal variants in the TCF7L2 gene

Ruiz-Narváez, Edward A.

doi:10.1038/ejhg.2014.17

Cited by 6 publications

(7 citation statements)

References 33 publications

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“…However, studies in Hispanic and African American populations [ 20 , 21 ], where LD between the two SNPs is weak or non-existent (Additional file 14 : Table S11 and Additional file 15 : Figures S8-S13), have reported association signals at both SNPs, with one study [ 21 ] showing that, in Hispanics, rs12255372 yields a stronger T2D-signal than rs7903146. These studies suggest a role for rs12255372 as an independent T2D-signal in TCF7L2 ; and both SNPs may be functionally significant, as both reside in independent, predicted enhancer sites [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Multiethnic genome-wide association study identifies ethnic-specific associations with body mass index in Hispanics and African Americans

2016

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BackgroundGenome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Therefore, our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. To that end, we conducted ethnic-specific genome-wide association analyses among 1235 Hispanic, 706 Asian, 1549 African American, and 2395 European American subjects from the Multi-ethnic Study of Atherosclerosis (MESA). We compared findings across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women’s Health Initiative (WHI).ResultsWe identified a genome-wide significant association in MESA Hispanics—rs12253976 in KLF6 (beta = 5.792 kg/m2 per-allele, 95 % confidence interval (CI): 3.885, 7.698; p = 3.43 × 10−9)—and suggestive SNPs with p < 5 × 10−6 in MESA Hispanics, European Americans and African Americans that display ethnic-specific effects on BMI. Of these suggestive SNPs, Hispanic SNP rs12255372 and African American SNP rs6435678 had the most evidence of replication in WHI. rs12255372 (in TCF7L2) was associated with lower BMI in both MESA (beta = −1.111 kg/m2, 95 % CI: −1.578, −0.645; p = 3.33 × 10−6) and WHI Hispanics (beta = −0.304 kg/m2, 95 % CI: −0.613, 0.006; p = 0.054). This TCF7L2 intronic region contains several SNPs (rs7901695, rs4506565, rs4132670, and rs12243326) with low p-values (p < 10−3) in MESA and betas of similar magnitude and direction in MESA and WHI, but only rs12243326 is in strong linkage disequilibrium with rs12255372 in our Hispanic populations, suggesting independent signals in this region. rs6435678 (in ERBB4) was associated with greater BMI in both MESA (beta = 1.104 kg/m2, 95 % CI: 0.643, 1.564; p = 2.85 × 10−6) and WHI African Americans (beta = 0.219 kg/m2, 95 % CI: −0.021, 0.460; p = 0.074).ConclusionsTwo BMI-association signals are present in the TCF7L2 intronic region of Hispanics, one of which is tagged by rs12255372. ERBB4 rs6435678 is a novel BMI-association signal in African Americans. Overall, our data suggest that ethnic-specific associations are involved in the genetic determination of BMI. Ethnic-specificity has potential implications for the development of gene-based therapies for obesity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0387-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Multiethnic genome-wide association study identifies ethnic-specific associations with body mass index in Hispanics and African Americans

2016

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“…Functional redundancy of enhancers has been observed in other contexts; for example, in the Drosophila genome, they have been termed shadow enhancers and have been suggested to allow for evolutionary variation in expression levels or developmental patterns while maintaining critical expression of their target genes (Jeong et al 2006;Hong et al 2008;Frankel et al 2010;Perry et al 2010;Cannavo et al 2016). In addition, redundant enhancers have been observed in mammalian genomes where they can function to coordinately maintain a critical threshold of expression and may in some cases buffer genetic variation across populations (Xiong et al 2002;Werner et al 2007;Corradin et al 2014;Ruiz-Narvaez 2014;Lam et al 2015). Based on our data, we propose that the ensemble of enhancers within a super-enhancer do not regulate higher transcription of their target genes compared to enhancers or act synergistically with each other but serve as partially redundant regulatory elements that allow for flexibility in cis-regulatory control that can fine tune transcriptional output of a target gene.…”

Section: Enhancer and Super-enhancer Equivalencementioning

confidence: 99%

Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes

et al. 2016

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Transcriptional enhancers are critical for maintaining cell-type-specific gene expression and driving cell fate changes during development. Highly transcribed genes are often associated with a cluster of individual enhancers such as those found in locus control regions. Recently, these have been termed stretch enhancers or super-enhancers, which have been predicted to regulate critical cell identity genes. We employed a CRISPR/Cas9-mediated deletion approach to study the function of several enhancer clusters (ECs) and isolated enhancers in mouse embryonic stem (ES) cells. Our results reveal that the effect of deleting ECs, also classified as ES cell super-enhancers, is highly variable, resulting in target gene expression reductions ranging from 12% to as much as 92%. Partial deletions of these ECs which removed only one enhancer or a subcluster of enhancers revealed partially redundant control of the regulated gene by multiple enhancers within the larger cluster. Many highly transcribed genes in ES cells are not associated with a super-enhancer; furthermore, super-enhancer predictions ignore 81% of the potentially active regulatory elements predicted by cobinding of five or more pluripotency-associated transcription factors. Deletion of these additional enhancer regions revealed their robust regulatory role in gene transcription. In addition, select super-enhancers and enhancers were identified that regulated clusters of paralogous genes. We conclude that, whereas robust transcriptional output can be achieved by an isolated enhancer, clusters of enhancers acting on a common target gene act in a partially redundant manner to fine tune transcriptional output of their target genes.

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“…In conclusion, FT seems to be regulated by multiple enhancers that seem to have an additive effect on flowering time in inductive conditions. The presence of multiple enhancers seems to be the rule rather than the exception in animals but has not yet been previously demonstrated in plants [32][33][34][35] . Enhancer characterization using reporter gene assays may easily overlook such redundant regulatory regions; furthermore, their requirement may be dependent on the genomic context.…”

Section: Discussionmentioning

confidence: 89%

Targeted DNA methylation represses two enhancers of FLOWERING LOCUS T in Arabidopsis thaliana

et al. 2019

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Redundant enhancers and causal variants in the TCF7L2 gene

Cited by 6 publications

References 33 publications

Multiethnic genome-wide association study identifies ethnic-specific associations with body mass index in Hispanics and African Americans

Multiethnic genome-wide association study identifies ethnic-specific associations with body mass index in Hispanics and African Americans

Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes

Targeted DNA methylation represses two enhancers of FLOWERING LOCUS T in Arabidopsis thaliana

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