EnhancerAtlas: a resource for enhancer annotation and analysis in 105 human cell/tissue types

Gao, Tianshun; He, Bing; Liu, Sheng; Zhu, Heng; Tan, Kai; Qian, Jiang

doi:10.1093/bioinformatics/btw495

Cited by 161 publications

(149 citation statements)

References 26 publications

(27 reference statements)

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“…In this regard, it was somewhat remarkable that 3 variations in distinct linkage blocks strongly associated with IBD (ORs 2.1-4.3), strengthening the validity of each association. This association, however, does not indicate the causality of these SNPs, which is unlikely for the intronic SNPs rs10846086 and rs2889504, which do not fall into regions of high genetic conservation or known genetic enhancers of transcription (36). Neither does SNP rs12815313 in the 5# untranslated region (NM_001286233.1:c.-171G .…”

Section: Discussionmentioning

confidence: 94%

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The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

Shaghaghi

Zhouyao

et al. 2017

The American Journal of Clinical Nutrition

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Background: Variations in intestinal antioxidant membrane transporters are implicated in the initiation and progression of inflammatory bowel disease (IBD). Facilitated glucose transporter member 14 (GLUT14), encoded by the solute carrier family 2 member 14 (SLC2A14) gene, is a putative transporter for dehydroascorbic acid and glucose. Although information on the gene is limited, shorter and longer GLUT14 isoforms have been identified. We hypothesized that GLUT14 mediates glucose and dehydroascorbic acid uptake. If this function could be validated, then genetic variations may associate with IBD. Objective: This study aimed to determine the substrate(s) for the GLUT14 protein and interrogated genetic associations of SLC2A14 with IBD. Design: The uptake of radiolabeled substrates into Xenopus laevis oocytes expressing the 2 GLUT14 isoforms was assessed. Examination of gene-targeted genetic association in the Manitoba Inflammatory Bowel Disease Cohort Study was conducted through the genotyping of single nucleotide polymorphisms (SNPs) representing linkage blocks of the SLC2A14 gene. Results: Both GLUT14 isoforms mediated the uptake of dehydroascorbic acid and glucose into X. laevis oocytes. Three alleles in the SLC2A14 gene associated independently with IBD. The odds of having ulcerative colitis (UC) or Crohn disease (CD) were elevated in carriers of the SLC2A14 SNP rs2889504-T allele (OR: 3.60; 95% CI: 1. 95, 6.64 and OR: 4.68; 95% CI: 2.78, 8.50, respectively). Similarly, the SNP rs10846086-G allele was associated with an increased risk of both UC and CD (OR: 2.91; 95% CI: 1.49, 5.68 and OR: 3.00; 95% CI: 1.55, 5.78, respectively). Moreover, the SNP rs12815313-T allele associated with increased susceptibility to CD and UC (OR: 2.12; 95% CI: 1.33, 3.36 and OR: 1.61; 95% CI: 1.01, 2.57, respectively). Conclusion: These findings strengthen the hypothesis that genetically determined local dysregulation of dietary vitamin C or antioxidants transport contributes to IBD development. These transporter proteins are targetable by dietary interventions, opening the avenue to a precision intervention for patients of specific genotypes with IBD. This trial was registered at clinicaltrials.gov as NCT03262649.Am J Clin Nutr 2017;106:1508-13.

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Section: Discussionmentioning

confidence: 94%

“…Neither does SNP rs12815313 in the 5# untranslated region (NM_001286233.1:c.-171G . A) affect any known transcription factors or enhancer binding sites (36,37). As such, future studies to identify causal SNPs are warranted.…”

Section: Discussionmentioning

confidence: 99%

The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

Shaghaghi

Zhouyao

et al. 2017

The American Journal of Clinical Nutrition

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“…To evaluate the proportion of CNEs that may be acting as enhancers, we analysed downloaded enhancer RNA (eRNA) data from the fetal brain generated by the FANTOM5 consortium 32 and predicted fetal brain enhancers from EnhancerAtlas 33 , which combines multiple sources of data to identify enhancers in different tissues. We used the experimentally validated fetal brain-active VISTA enhancers to estimate this sensitivity of each data set.…”

Section: Methodsmentioning

confidence: 99%

“…5a). Analysis of the FANTOM5 32 and EnhancerAtlas 33 datasets suggests that 50-70% of the fetal brain-active CNEs act as enhancers (see Methods).…”

Section: Enrichment Of Mutations In Non-coding Elementsmentioning

confidence: 99%

De novo mutations in regulatory elements in neurodevelopmental disorders

Short

McRae

Gallone

et al. 2018

Nature

239

219

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We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.

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“…(B) Enhanceratlas.org tracks (accessed December, 2016) display chromatin loops observed in CD14 monocytes at this locus, providing a three-dimensional framework for potential enhancer-promoter interactions [65]. Knock-down of 774 and 775 affected acquisition of H3K4me2 (C), H3K27ac (D), H3K4me3 (E), and H3K4me2 (F) at Enhancer 1 (left panels) and to a lesser degree extent at the promoter (middle panels) after LPS.…”

Section: Figurementioning

confidence: 99%

SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs

Shii

Song

Maurer

et al. 2017

Molecular Immunology

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The SERPINB2 gene is strongly upregulated in inflammatory states. In monocytes, it can constitute up to 1% of total cellular protein. It functions in protection from proteotoxic stress and plays a role in angioedema. The purpose of this study was to define the roles of enhancer RNAs embedded in the SERPIN gene complex. We found that the upstream enhancer RNAs upregulated SERPINB2 and the enhancer RNAs were expressed prior to those of SERPINB2 mRNA. Studies of the SERPINB2 promoter demonstrated the presence of an RNA polymerase II pause-inducing protein, NELF. Stimulation with LPS led to recruitment of the pause-releasing kinase P-TEFb and departure of the pause-inducing protein NELF. RNA immunoprecipitation revealed that NELF and the CDK9 component of P-TEFb bound to the enhancer RNAs after stimulation with distinct kinetics. Knock-down of the enhancer RNAs compromised stimulus induction of promoter and enhancer chromatin changes. Conversely, over-expression was associated with enhanced recruitment of c-JUN and increased expression of SERPINB2 mRNA expression. This study is the first to associate enhancer RNAs with SERPINB2 and is the first demonstration of acquisition of NELF binding by enhancer RNAs on chromatin.

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EnhancerAtlas: a resource for enhancer annotation and analysis in 105 human cell/tissue types

Cited by 161 publications

References 26 publications

The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

De novo mutations in regulatory elements in neurodevelopmental disorders

SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs

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