Enhancers regulate progression of development in mammalian cells

Kranz, Anna Lena; Eils, Roland; König, Rainer

doi:10.1093/nar/gkr602

Cited by 8 publications

(7 citation statements)

References 83 publications

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“…Strong enhancers regulating distal genes (Figure 3) were also enriched for trait-associated SNPs, albeit less so than strong enhancers which regulate proximal genes (Figure 3). Conserved distal regulatory enhancers are frequently found at loci containing developmental genes [25,26]. The results presented here may therefore reflect the depletion of variants in such enhancers due to their detrimental effects upon developmental processes.…”

Section: Resultsmentioning

confidence: 75%

The genomic signature of trait-associated variants

et al. 2013

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BackgroundGenome-wide association studies have identified thousands of SNP variants associated with hundreds of phenotypes. For most associations the causal variants and the molecular mechanisms underlying pathogenesis remain unknown. Exploration of the underlying functional annotations of trait-associated loci has thrown some light on their potential roles in pathogenesis. However, there are some shortcomings of the methods used to date, which may undermine efforts to prioritize variants for further analyses. Here, we introduce and apply novel methods to rigorously identify annotation classes showing enrichment or depletion of trait-associated variants taking into account the underlying associations due to co-location of different functional annotations and linkage disequilibrium.ResultsWe assessed enrichment and depletion of variants in publicly available annotation classes such as genic regions, regulatory features, measures of conservation, and patterns of histone modifications. We used logistic regression to build a multivariate model that identified the most influential functional annotations for trait-association status of genome-wide significant variants. SNPs associated with all of the enriched annotations were 8 times more likely to be trait-associated variants than SNPs annotated with none of them. Annotations associated with chromatin state together with prior knowledge of the existence of a local expression QTL (eQTL) were the most important factors in the final logistic regression model. Surprisingly, despite the widespread use of evolutionary conservation to prioritize variants for study we find only modest enrichment of trait-associated SNPs in conserved regions.ConclusionWe established odds ratios of functional annotations that are more likely to contain significantly trait-associated SNPs, for the purpose of prioritizing GWAS hits for further studies. Additionally, we estimated the relative and combined influence of the different genomic annotations, which may facilitate future prioritization methods by adding substantial information.

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Section: Resultsmentioning

confidence: 75%

The genomic signature of trait-associated variants

et al. 2013

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“…Moreover, there is no reason to suppose that, if present, sample degradation would have occurred in any but a random distribution across the cohort and therefore should not have led to erroneous associations. Second, the methylation sites studied were upstream from the proximal promoter region, but they were located in a region that has been demonstrated to contain positive regulatory elements of transcription and there are several studies reporting promoter regulation by sites at this distance . We excluded the presence of an SNP at the CpG sites of interest by sequencing, but without genomewide analysis it is not possible to exclude a genetic effect of distant SNPs that could influence both DNA methylation of a particular sequence and a child's phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Second, the methylation sites studied were upstream from the proximal promoter region, but they were located in a region that has been demonstrated to contain positive regulatory elements of transcription (15) and there are several studies reporting promoter regulation by sites at this distance. (24,25) We excluded the presence of an SNP at the CpG sites of interest by sequencing, but without genomewide analysis it is not possible to exclude a genetic effect of distant SNPs that could influence both DNA methylation of a particular sequence and a child's phenotype. Third, we analyzed methylation in cells from whole umbilical cord; whereas it is possible that the differential methylation we observed arose from variation in the proportions of different component cells (eg, fibroblasts, epithelial cells) in individual samples, our studies show similar methylation in different umbilical cord cell types (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Childhood Bone Mineral Content Is Associated With Methylation Status of the RXRA Promoter at Birth

Harvey

Sheppard

Godfrey

et al. 2013

Journal of Bone and Mineral Research

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Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X receptor-alpha (RXRA) is an essential cofactor in the action of 1,25-dihydroxyvitamin D (1,25[OH] 2 -vitamin D), and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual-energy X-ray absorptiometry, in a population-based motheroffspring cohort (Southampton Women's Survey). Relationships between maternal plasma 25-hydroxyvitamin D (25[OH]-vitamin D) concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, a higher percent methylation at four of six RXRA CpG sites measured was correlated with lower offspring bone mineral content (BMC) corrected for body size (b ¼ À2.1 to À3.4 g/SD, p ¼ 0.002 to 0.047). In a second independent cohort (n ¼ 64), similar negative associations at two of these CpG sites, but positive associations at the two remaining sites, were observed; however, none of the relationships in this replication cohort achieved statistical significance. The maternal free 25(OH)-vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (b ¼ À3.3 SD/unit, p ¼ 0.03). Thus, perinatal epigenetic marking at the RXRA promoter region in umbilical cord was inversely associated with offspring size-corrected BMC in childhood. The potential mechanistic and functional significance of this finding remains a subject for further investigation.

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“…For example, Sp1 trans-activates the genes encoding filtrin (18) and podocalyxin (5) specifically in podocytes. Sp1 is critically involved in epithelial-mesenchymal transition transcriptional networks (22), control of circadian clock genes (13), and tops the list of promoter-enhancer modules involved in differentiation of human stem cells (12). As other examples, Sp1 is part of the TNF-␣ enhanceosome (21), controls a variety of estrogen-inducible genes (23), and the glucocorticoid responsiveness of the AT1b receptor gene (2).…”

Section: Discussionmentioning

confidence: 99%

Sp1 trans-activates and is required for maximal aldosterone induction of the αENaC gene in collecting duct cells

Kong

Kone

2013

American Journal of Physiology-Renal Physiology

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Yu Z, Kong Q, Kone BC. Sp1 trans-activates and is required for maximal aldosterone induction of the ␣ENaC gene in collecting duct cells. Am J Physiol Renal Physiol 305: F653-F662, 2013. First published June 26, 2013 doi:10.1152/ajprenal.00177.2013.-The epithelial Na ϩ channel (ENaC) in the distal nephron constitutes the rate-limiting step for renal sodium reabsorption. Aldosterone increases tubular sodium absorption in large part by increasing ␣ENaC transcription in collecting duct principal cells. We previously reported that Af9 binds to ϩ78/ϩ92 of ␣ENaC and recruits Dot1a to repress basal and aldosterone-sensitive ␣ENaC transcription in mouse inner medullary collecting duct (mIMCD)3 cells. Despite this epigenetic repression, basal ␣ENaC transcription is still evident and physiologically necessary, indicating basal operation of positive regulators. In the present study, we identified Sp1 as one such regulator. Gel shift and antibody competition assays using a ϩ208/ϩ240 probe revealed DNA-Sp1-containing complexes in mIMCD3 cells. Mutation of the ϩ222/ϩ229 element abrogated Sp1 binding in vitro and in promoterreporter constructs stably expressed in mIMCD3 cells. Compared with the wild-type promoter, an ␣ENaC promoter-luciferase construct with ϩ222/ϩ229 mutations exhibited much lower activity and impaired trans-activation in Sp1 overexpression experiments. Conversely, Sp1 knockdown inhibited endogenous ␣ENaC mRNA and the activity of the wild-type ␣ENaC promoter but not the mutated construct. Aldosterone triggered Sp1 recruitment to the ␣ENaC promoter, which was required for maximal induction of ␣ENaC promoter activity and was blocked by spironolactone. Sequential chromatin immunoprecipitation assays and functional tests of ϩ78/ϩ92 and ϩ222/ϩ229 ␣ENaC promoter mutants indicated that while Sp1, Dot1a, and Af9 co-occupy the ␣ENaC promoter, the Sp1 effects are functionally independent from Dot1a and Af9. In summary, Sp1 binding to a cis-element at ϩ222/ϩ229 represents the first identified constitutive driver of ␣ENaC transcription, and it contributes to maximal aldosterone transactivation of ␣ENaC.

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Enhancers regulate progression of development in mammalian cells

Cited by 8 publications

References 83 publications

The genomic signature of trait-associated variants

The genomic signature of trait-associated variants

Childhood Bone Mineral Content Is Associated With Methylation Status of the RXRA Promoter at Birth

Sp1 trans-activates and is required for maximal aldosterone induction of the αENaC gene in collecting duct cells

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