Structural variation in the 3D genome

Spielmann, Malte; Lupiáñez, Darío G.; Mundlos, Stefan

doi:10.1038/s41576-018-0007-0

Cited by 528 publications

(552 citation statements)

References 146 publications

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“…Therefore, even the noncoding DNA regions could be essential for achieving the correct gene expression in planar chromatin. Strong support for this functional model comes from experiments showing that disruptions of noncoding regions cause gene misexpression and disease . I hope that this article will encourage other researchers to conduct further studies on the supramolecular organization of chromatin.…”

Section: Conclusion and Outlook: Supramolecular Versus Polymer Modelsmentioning

confidence: 81%

Supramolecular multilayer organization of chromosomes: possible functional roles of planar chromatin in gene expression and DNA replication and repair

Daban

2020

FEBS Letters

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Experimental evidence indicates that the chromatin filament is self‐organized into a multilayer planar structure that is densely stacked in metaphase and unstacked in interphase. This chromatin organization is unexpected, but it is shown that diverse supramolecular assemblies, including dinoflagellate chromosomes, are multilayered. The mechanical strength of planar chromatin protects the genome integrity, even when double‐strand breaks are produced. Here, it is hypothesized that the chromatin filament in the loops and topologically associating domains is folded within the thin layers of the multilaminar chromosomes. It is also proposed that multilayer chromatin has two states: inactive when layers are stacked and active when layers are unstacked. Importantly, the well‐defined topology of planar chromatin may facilitate DNA replication without entanglements and DNA repair by homologous recombination.

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Section: Conclusion and Outlook: Supramolecular Versus Polymer Modelsmentioning

confidence: 81%

Supramolecular multilayer organization of chromosomes: possible functional roles of planar chromatin in gene expression and DNA replication and repair

Daban

2020

FEBS Letters

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“…The gene‐dosage pathogenic effect is supported by our results on the Xq28 TADs structure. The rearrangements did not disturb any known TAD boundaries and accordingly could be classified as intra‐TAD duplications resulting in a gene‐dosage gain (Figure S4). GDI1, RPL10 and FLNA are actually overexpressed in affected individuals and highly expressed in brain .…”

Section: Resultsmentioning

confidence: 99%

Delineation of MidXq28‐duplication syndrome distal to MECP2 and proximal to RAB39B genes

et al. 2019

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Two distinct genomic disorders have been linked to Xq28‐gains, namely Xq28‐duplications including MECP2 and Int22h1/Int22h2‐mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28‐gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28‐duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.

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“…Structural variants (SVs) are a common cause of human congenital malformation syndromes and recent studies show that SVs can be pathogenic affecting protein coding genes and reshuffling the complex non-coding cis -regulatory architecture of the genome 1. One particularly interesting example is a rare homeotic transformation syndrome first described by Liebenberg in 1973 2.…”

Section: Introductionmentioning

confidence: 99%

H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome

et al. 2019

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BackgroundStructural variants (SVs) affecting non-coding cis-regulatory elements are a common cause of congenital limb malformation. Yet, the functional interpretation of these non-coding variants remains challenging. The human Liebenberg syndrome is characterised by a partial transformation of the arms into legs and has been shown to be caused by SVs at the PITX1 locus leading to its misregulation in the forelimb by its native enhancer element Pen. This study aims to elucidate the genetic cause of an unsolved family with a mild form of Liebenberg syndrome and investigate the role of promoters in long-range gene regulation.MethodsHere, we identify SVs by whole genome sequencing (WGS) and use CRISPR-Cas9 genome editing in transgenic mice to assign pathogenicity to the SVs.ResultsIn this study, we used WGS in a family with three mildly affected individuals with Liebenberg syndrome and identified the smallest deletion described so far including the first non-coding exon of H2AFY. To functionally characterise the variant, we re-engineered the 8.5 kb deletion using CRISPR-Cas9 technology in the mouse and showed that the promoter of the housekeeping gene H2afy insulates the Pen enhancer from Pitx1 in forelimbs; its loss leads to misexpression of Pitx1 by the pan-limb activity of the Pen enhancer causing Liebenberg syndrome.ConclusionOur data indicate that housekeeping promoters may titrate promiscuous enhancer activity to ensure normal morphogenesis. The deletion of the H2AFY promoter as a cause of Liebenberg syndrome highlights this new mutational mechanism and its role in congenital disease.

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Structural variation in the 3D genome

Cited by 528 publications

References 146 publications

Supramolecular multilayer organization of chromosomes: possible functional roles of planar chromatin in gene expression and DNA replication and repair

Supramolecular multilayer organization of chromosomes: possible functional roles of planar chromatin in gene expression and DNA replication and repair

Delineation of MidXq28‐duplication syndrome distal to MECP2 and proximal to RAB39B genes

H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome

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