Enhancer adoption caused by genomic insertion elicits interdigital
            <i>Shh</i>
            expression and syndactyly in mouse

Mouri, Kousuke; Sagai, Tomoko; Maeno, Akiteru; Amano, Takanori; Toyoda, Atsushi; Shiroishi, Toshihiko

doi:10.1073/pnas.1713339115

Cited by 15 publications

(8 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This results in overexpression of interdigital Shh, secondary suppression of the Bmp signaling, and finally syndactyly. The pathophysiology of this secondary suppression of Bmp was recently shown by Mouri et al [44]. The overexpression of Shh leads to the upregulation of Chordin.…”

Section: The Unified Pathway Of Pathogenesis Of Syndactylymentioning

confidence: 87%

See 1 more Smart Citation

A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis

Al‐Qattan

2019

BioMed Research International

View full text Add to dashboard Cite

Embryology of normal web space creation and the genetics of syndactyly in humans and experimental animals are well described in the literature. In this review, the author offers a 3-step pathway of pathogenesis for syndactyly. The first step is initiated either by the overactivation of the WNT canonical pathway or the suppression of the Bone Morphogenetic Protein (BMP) canonical pathway. This leads to an overexpression of Fibroblast Growth Factor 8 (FGF8). The final step is the suppression of retinoic acid in the interdigital mesenchyme leading to suppression of both apoptosis and extracellular matrix (ECM) degradation, resulting in syndactyly.

show abstract

Section: The Unified Pathway Of Pathogenesis Of Syndactylymentioning

confidence: 87%

“…The overexpression of Shh leads to the upregulation of Chordin. Chordin binds to Bmps and sequestrates them into latent complexes, thereby suppressing the Bmp activity [44].…”

Section: The Unified Pathway Of Pathogenesis Of Syndactylymentioning

confidence: 99%

A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis

Al‐Qattan

2019

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…Ectopic enhancer adoption is a disease mechanism that has been observed in similar genomic rearrangements. A recent study using the Hammer toe mouse model, which displays a syndactyly phenotype, identified a large interchromosomal insertion occurring upstream of the sonic hedgehog (Shh) gene which contains enhancer elements that drive ectopic Shh expression during limb development (Mouri et al, 2018).…”

Section: The Disease-associated Insertions At Xq271 Can Disrupt Long-...mentioning

confidence: 99%

Structural Variation at a Disease Mutation Hotspot: Strategies to Investigate Gene Regulation and the 3D Genome

2022

View full text Add to dashboard Cite

A rare form of X-linked Charcot-Marie-Tooth neuropathy, CMTX3, is caused by an interchromosomal insertion occurring at chromosome Xq27.1. Interestingly, eight other disease phenotypes have been associated with insertions (or insertion-deletions) occurring at the same genetic locus. To date, the pathogenic mechanism underlying most of these diseases remains unsolved, although local gene dysregulation has clearly been implicated in at least two phenotypes. The challenges of accessing disease-relevant tissue and modelling these complex genomic rearrangements has led to this research impasse. We argue that recent technological advancements can overcome many of these challenges, particularly induced pluripotent stem cells (iPSC) and their capacity to provide access to patient-derived disease-relevant tissue. However, to date these valuable tools have not been utilized to investigate the disease-associated insertions at chromosome Xq27.1. Therefore, using CMTX3 as a reference disease, we propose an experimental approach that can be used to explore these complex mutations, as well as similar structural variants located elsewhere in the genome. The mutational hotspot at Xq27.1 is a valuable disease paradigm with the potential to improve our understanding of the pathogenic consequences of complex structural variation, and more broadly, refine our knowledge of the multifaceted process of long-range gene regulation. Intergenic structural variation is a critically understudied class of mutation, although it is likely to contribute significantly to unsolved genetic disease.

show abstract

“…Classically these methods were low throughput, laborious and restricted to a limited set of genetic models (Bender et al 2000;Bauer et al 2013). CRISPR genome-editing is rapid and has been adapted for use in a larger array of organisms, allowing for the investigation of conserved non-coding elements across different species through parallel loss-of-function approaches (Kvon et al 2016;Letelier et al 2018;Mouri et al 2018). CRISPR deletion of enhancers in model organisms has clarified the redundant function of individual enhancers within super-enhancer clusters (Hay et al 2016;Shin et al 2016;Preissl et al 2018).…”

Section: Enhancer Perturbation and Knockout Approachesmentioning

confidence: 99%

Transcriptional enhancers: from prediction to functional assessment on a genome-wide scale

Tobias

Abatti

Moorthy

et al. 2021

Genome

View full text Add to dashboard Cite

Enhancers are cis-regulatory sequences located distally to target genes. These sequences consolidate developmental and environmental cues to coordinate gene expression in a tissue-specific manner. Enhancer function and tissue specificity depend on the expressed set of transcription factors, which recognize binding sites and recruit cofactors that regulate local chromatin organization and gene transcription. Unlike other genomic elements, enhancers are challenging to identify because they function independently of orientation, are often distant from their promoters, have poorly defined boundaries and display no reading frame. In addition, there are no defined genetic or epigenetic features that are unambiguously associated with enhancer activity. Over recent years there have been developments in both empirical assays and computational methods for enhancer prediction. We review genome-wide tools, CRISPR advancements and high-throughput screening approaches that have improved our ability to both observe and manipulate enhancers in vitro at the level of primary genetic sequences, chromatin states and spatial interactions. We also highlight contemporary animal models and their importance to enhancer validation. Together, these experimental systems and techniques complement one another and broaden our understanding of enhancer function in development, evolution, and disease.

show abstract

Enhancer adoption caused by genomic insertion elicits interdigital Shh expression and syndactyly in mouse

Cited by 15 publications

References 50 publications

A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis

A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis

Structural Variation at a Disease Mutation Hotspot: Strategies to Investigate Gene Regulation and the 3D Genome

Transcriptional enhancers: from prediction to functional assessment on a genome-wide scale

Contact Info

Product

Resources

About