Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog)

Will, Anja J.; Cova, Giulia; Osterwalder, Marco; Chan, Wing-Lee; Wittler, Lars; Brieske, Norbert; Heinrich, Verena; Villartay, Jean‐Pierre de; Vingron, Martin; Klopocki, Eva; Visel, Axel; Lupiáñez, Darío G.; Mundlos, Stefan

doi:10.1038/ng.3939

Cited by 115 publications

(127 citation statements)

References 40 publications

(53 reference statements)

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“…Studies of individual loci have identified examples of mammalian enhancers near the same gene with remarkably similar spatiotemporal activity patterns or functions 15,27–32 , reminiscent of invertebrate “shadow enhancers” 8,9,33–35 . The lack of dramatic morphological phenotypes in our enhancer deletion mouse models suggests that panels of mammalian enhancers with large degrees of redundancy act as a regulatory buffer for key developmental processes, thereby reducing the likelihood of severe consequences from genetic or environmental challenges 8 .…”

Section: Textmentioning

confidence: 99%

Enhancer redundancy provides phenotypic robustness in mammalian development

Osterwalder

Barozzi

Tissières

et al. 2018

Nature

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538

536

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Summary Distant-acting tissue-specific enhancers vastly outnumber protein-coding genes in mammalian genomes, but the functional significance of this regulatory complexity remains insufficiently understood1,2. Here we show that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. We used genome editing to create 23 mouse deletion lines and inter-crosses, including both single and combinatorial enhancer deletions at seven distinct loci required for limb development. Surprisingly, none of ten deletions of individual enhancers caused noticeable changes in limb morphology. In contrast, removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genome-wide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of three representative developmental structures (limb, brain, heart) uncovered more than a thousand cases in which five or more enhancers with redundant activity patterns were found near the same gene. Taken together, our data indicate that enhancer redundancy is a remarkably widespread feature of mammalian genomes and provides an effective regulatory buffer preventing deleterious phenotypic consequences upon loss of individual enhancers.

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Section: Textmentioning

confidence: 99%

Enhancer redundancy provides phenotypic robustness in mammalian development

Osterwalder

Barozzi

Tissières

et al. 2018

Nature

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538

536

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“…Figures 3A and B and The nine mouse enhancer data used for analyses displayed in Figure 3C and Suppl. Figure S11 were obtained from Will et al 37 (https://media.nature.com/original/natureassets/ng/journal/v49/n10/extref/ng.3939-S1.pdf, Supplementary Table S4). The mouse coordinates were mapped to human using CrossMap (v.0.2.5.…”

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confidence: 99%

“…Next, we chose a human disease that involves the rearrangement of the regulatory landscape of IHH (encoding Indian hedgehog), which cause developmental defects including craniosynostosis and synpolydactyly 35,36 . Will et al 37 identified nine enhancers with individual tissue specificities in the digit anlagen, growth plates, skull sutures and fingertips. The IHH region in humans shares a common structure with the mouse locus that was used for the model by Will et al 37 In their study, consecutive deletions resulted in growth defects of the skull and long bones that confirmed that the enhancers function in an additive manner.…”

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confidence: 99%

“…Will et al 37 identified nine enhancers with individual tissue specificities in the digit anlagen, growth plates, skull sutures and fingertips. The IHH region in humans shares a common structure with the mouse locus that was used for the model by Will et al 37 In their study, consecutive deletions resulted in growth defects of the skull and long bones that confirmed that the enhancers function in an additive manner. Deletions and duplications caused dose-dependent upregulation and misexpression of Ihh, leading to abnormal phalanges, fusion of sutures and syndactyly.…”

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confidence: 99%

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Identification of essential regulatory elements in the human genome

Wells

Heckerman

Torkamani

et al. 2018

Preprint

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The identification of essential regulatory elements is central to the understanding of the consequences of genetic variation. Here we use novel genomic data and machine learning techniques to map essential regulatory elements and to guide functional validation. We train an XGBoost model using 38 functional and structural features, including genome essentiality metrics, 3D genome organization and enhancer reporter STARR-seq data to differentiate between pathogenic and control non-coding genetic variants. We validate the accuracy of prediction by using data from tiling-deletion-based and CRISPR interference screens of activity of cis-regulatory elements. In neurodevelopmental disorders, the model (ncER, non-coding Essential Regulation) maps essential genomic segments within deletions and rearranged topologically associated domains linked to human disease. We show that the approach successfully identifies essential regulatory elements in the human genome.

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“…This contrasts other loci, where robustness is mainly ensured via the additive effect of multiple, partially redundant enhancers. At the Hoxd and Ihh loci for example, several enhancers have been shown to globally contribute to the final transcription pattern(44)(45)(46)(47). At these loci, a preformed interaction may be unnecessary as a promoter samples the cumulative activities of all its enhancers, each of which possesses an overlapping and redundant activity.…”

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confidence: 99%

Preformed Chromatin Topology Assists Transcriptional Robustness ofShhduring Limb Development

Paliou¹,

Guckelberger²,

Schöpflin³

et al. 2019

Preprint

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Long-range gene regulation involves physical proximity between enhancers and promoters to generate precise patterns of gene expression in space and time. However, in some cases proximity coincides with gene activation, whereas in others preformed topologies already exist before activation. In this study, we investigate the preformed configuration underlying the regulation of the Shh gene by its unique limb enhancer, the ZRS, in vivo during mouse development. Abrogating the constitutive transcription covering the ZRS region led to a shift within the Shh-ZRS contacts and a moderate reduction in Shh transcription. Deletion of the CTCF binding sites around the ZRS resulted in a loss of the Shh-ZRS preformed interaction and a 50% decrease in Shh expression but no phenotype, suggesting an additional, CTCFindependent mechanism of promoter-enhancer communication. This residual activity, however, was diminished by combining the loss of CTCF binding with a hypomorphic ZRS allele resulting in severe Shh loss-of-function and digit agenesis. Our results indicate that the preformed chromatin structure of the Shh locus is sustained by multiple components and acts to reinforce enhancer-promoter communication for robust transcription.

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Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog)

Cited by 115 publications

References 40 publications

Enhancer redundancy provides phenotypic robustness in mammalian development

Enhancer redundancy provides phenotypic robustness in mammalian development

Identification of essential regulatory elements in the human genome

Preformed Chromatin Topology Assists Transcriptional Robustness ofShhduring Limb Development

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