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  • 1
    Language: English
    In: Cell, 2015-05-21, Vol.161 (5), p.1012-1025
    Description: Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome. [Display omitted] •Disruptions of TADs lead to de novo enhancer-promoter interactions and misexpression•Misexpression occurs when CTCF-associated TAD boundary elements are disrupted•Structural variations disrupting TAD structures can cause malformation syndromes•Different phenotypes can result from one enhancer acting on different target genes Disease-associated structural variants, when affecting CTCF-associated boundary elements, cause pathogenicity by disrupting the structure of topologically associated chromatin domains leading to ectopic promoter interactions and altered gene expression.
    Subject(s): Animals ; Chromatin ; Disease Models, Animal ; Enhancer Elements, Genetic ; Extremities - anatomy & histology ; Extremities - growth & development ; Gene expression ; Gene Expression Regulation ; Genes ; Genomics ; Humans ; Limb Deformities, Congenital - genetics ; Medical genetics ; Mice ; Noncoding DNA ; Promoter Regions, Genetic ; Receptor, EphA4 - genetics ; RNA, Untranslated - genetics ; RNA, Untranslated - metabolism
    ISSN: 0092-8674
    E-ISSN: 1097-4172
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
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  • 2
    Language: English
    In: Nature (London), 2016-10-13, Vol.538 (7624), p.265-269
    Description: Chromosome conformation capture methods have identified subchromosomal structures of higher-order chromatin interactions called topologically associated domains (TADs) that are separated from each other by boundary regions. By subdividing the genome into discrete regulatory units, TADs restrict the contacts that enhancers establish with their target genes. However, the mechanisms that underlie partitioning of the genome into TADs remain poorly understood. Here we show by chromosome conformation capture (capture Hi-C and 4C-seq methods) that genomic duplications in patient cells and genetically modified mice can result in the formation of new chromatin domains (neo-TADs) and that this process determines their molecular pathology. Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans, showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure. In contrast, overlapping duplications that extended over the next boundary into the neighbouring TAD (inter-TAD), resulted in the formation of a new chromatin domain (neo-TAD) that was isolated from the rest of the genome. As a consequence of this insulation, inter-TAD duplications had no phenotypic effect. However, incorporation of the next flanking gene, Kcnj2, in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype. Our findings provide evidence that TADs are genomic regulatory units with a high degree of internal stability that can be sculptured by structural genomic variations. This process is important for the interpretation of copy number variations, as these variations are routinely detected in diagnostic tests for genetic disease and cancer. This finding also has relevance in an evolutionary setting because copy-number differences are thought to have a crucial role in the evolution of genome complexity.
    Subject(s): Animals ; Chromatin ; Chromatin Assembly and Disassembly - genetics ; Disease - genetics ; DNA - genetics ; DNA Copy Number Variations - genetics ; DNA replication ; Facies ; Female ; Fibroblasts ; Fingers - abnormalities ; Foot Deformities, Congenital - genetics ; Gene Duplication - genetics ; Gene Expression ; Genomics ; Hand Deformities, Congenital - genetics ; Male ; Mice ; Observations ; Phenotype ; Physiological aspects ; SOX9 Transcription Factor - genetics
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Get It Now
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  • 3
    Language: English
    In: Genome research, 2017-02, Vol.27 (2), p.223-233
    Description: Complex regulatory landscapes control the pleiotropic transcriptional activities of developmental genes. For most genes, the number, location, and dynamics of their associated regulatory elements are unknown. In this work, we characterized the three-dimensional chromatin microarchitecture and regulatory landscape of 446 limb-associated gene loci in mouse using Capture-C, ChIP-seq, and RNA-seq in forelimb, hindlimb at three developmental stages, and midbrain. The fine mapping of chromatin interactions revealed a strong preference for functional genomic regions such as repressed or active domains. By combining chromatin marks and interaction peaks, we annotated more than 1000 putative limb enhancers and their associated genes. Moreover, the analysis of chromatin interactions revealed two regimes of chromatin folding, one producing interactions stable across tissues and stages and another one associated with tissue and/or stage-specific interactions. Whereas stable interactions associate strongly with CTCF/RAD21 binding, the intensity of variable interactions correlates with changes in underlying chromatin modifications, specifically at the viewpoint and at the interaction site. In conclusion, this comprehensive data set provides a resource for the characterization of hundreds of limb-associated regulatory landscapes and a framework to interpret the chromatin folding dynamics observed during embryogenesis.
    Subject(s): Animals ; Binding Sites ; Chromatin ; Chromatin - genetics ; Chromatin Immunoprecipitation ; Enhancer Elements, Genetic ; Extremities - growth & development ; Gene Expression Regulation, Developmental ; Genetic aspects ; Histones - genetics ; Mice ; Promoter Regions, Genetic ; Research ; RNA sequencing ; Rodents as pets ; Transcription Factors - genetics ; Transcriptional Activation - genetics
    ISSN: 1088-9051
    E-ISSN: 1549-5469
    Source: HighWire Press (Free Journals)
    Source: Hellenic Academic Libraries Link
    Source: Cold Spring Harbor Laboratory Press
    Source: PubMed Central
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  • 4
    Language: English
    In: Nature genetics, 2018-10, Vol.50 (10), p.1463-1473
    Description: The regulatory specificity of enhancers and their interaction with gene promoters is thought to be controlled by their sequence and the binding of transcription factors. By studying Pitx1, a regulator of hindlimb development, we show that dynamic changes in chromatin conformation can restrict the activity of enhancers. Inconsistent with its hindlimb-restricted expression, Pitx1 is controlled by an enhancer (Pen) that shows activity in forelimbs and hindlimbs. By Capture Hi-C and three-dimensional modeling of the locus, we demonstrate that forelimbs and hindlimbs have fundamentally different chromatin configurations, whereby Pen and Pitx1 interact in hindlimbs and are physically separated in forelimbs. Structural variants can convert the inactive into the active conformation, thereby inducing Pitx1 misexpression in forelimbs, causing partial arm-to-leg transformation in mice and humans. Thus, tissue-specific three-dimensional chromatin conformation can contribute to enhancer activity and specificity in vivo and its disturbance can result in gene misexpression and disease.
    Subject(s): Animal tissues ; Arm ; Chromatin ; Conformation ; Enhancers ; Evolution & development ; Extremities (Anatomy) ; Gene expression ; Genomes ; Health aspects ; Morphogenesis ; Pituitary gland ; Polymer melts ; Research ; Rodents ; Sensors ; Stem cells ; Three dimensional models ; Transcription factors ; Transformation
    ISSN: 1061-4036
    E-ISSN: 1546-1718
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Nature cell biology, 2019-03-01, Vol.21 (3), p.305-310
    Description: Balanced chromosomal rearrangements such as inversions and translocations can cause congenital disease or cancer by inappropriately rewiring promoter-enhancer contacts(1,2). To study the potentially pathogenic consequences of balanced chromosomal rearrangements, we generated a series of genomic inversions by placing an active limb enhancer cluster from the Epha4 regulatory domain at different positions within a neighbouring gene-dense region and investigated their effects on gene regulation in vivo in mice. Expression studies and high-throughput chromosome conformation capture from embryonic limb buds showed that the enhancer cluster activated several genes downstream that are located within asymmetric regions of contact, the so-called architectural stripes(3). The ectopic activation of genes led to a limb phenotype that could be rescued by deleting the CCCTC-binding factor (CTCF) anchor of the stripe. Architectural stripes appear to be driven by enhancer activity, because they do not form in mouse embryonic stem cells. Furthermore, we show that architectural stripes are a frequent feature of developmental three-dimensional genome architecture often associated with active enhancers. Therefore, balanced chromosomal rearrangements can induce ectopic gene expression and the formation of asymmetric chromatin contact patterns that are dependent on CTCF anchors and enhancer activity.
    Subject(s): Birth defects ; Cancer ; Cell Biology ; Chromatin ; Chromosome rearrangements ; Chromosome translocations ; Clusters ; Conformation ; Congenital defects ; Embryo cells ; Enhancers ; EphA4 protein ; Gene expression ; Gene regulation ; Genes ; Genetic aspects ; Genetic disorders ; Genetic engineering ; Genetic research ; Genomes ; Genomic structural variations ; Health aspects ; In vivo methods and tests ; Inversions ; Kinases ; Life Sciences & Biomedicine ; Limb buds ; Phenotypes ; Research ; Rewiring ; Science & Technology ; Stem cell transplantation ; Stem cells ; Transcription activation
    ISSN: 1465-7392
    E-ISSN: 1476-4679
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Get It Now
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  • 6
    Language: English
    In: Nature genetics, 2017-10, Vol.49 (10), p.1539-1545
    Description: Copy number variations (CNVs) often include noncoding sequences and putative enhancers, but how these rearrangements induce disease is poorly understood. Here we investigate CNVs involving the regulatory landscape of IHH (encoding Indian hedgehog), which cause multiple, highly localized phenotypes including craniosynostosis and synpolydactyly. We show through transgenic reporter and genome-editing studies in mice that Ihh is regulated by a constellation of at least nine enhancers with individual tissue specificities in the digit anlagen, growth plates, skull sutures and fingertips. Consecutive deletions, resulting in growth defects of the skull and long bones, showed that these enhancers function in an additive manner. Duplications, in contrast, caused not only dose-dependent upregulation but also misexpression of Ihh, leading to abnormal phalanges, fusion of sutures and syndactyly. Thus, precise spatiotemporal control of developmental gene expression is achieved by complex multipartite enhancer ensembles. Alterations in the composition of such clusters can result in gene misexpression and disease.
    Subject(s): Abnormalities ; Animals ; Base Sequence ; Binding sites ; Bioinformatics ; Bone Diseases, Developmental - genetics ; Bones ; Copy number ; Copy number variations ; Craniosynostosis ; Deoxyribonucleic acid ; Development and progression ; Developmental stages ; DNA ; DNA Copy Number Variations ; DNA repair ; DNA-Binding Proteins - deficiency ; DNA-Binding Proteins - genetics ; Dosage ; Enhancer Elements, Genetic - genetics ; Enhancers ; Foot Deformities, Congenital - genetics ; Gene Deletion ; Gene Dosage ; Gene Duplication ; Gene expression ; Gene Expression Regulation, Developmental - genetics ; Gene Knockout Techniques ; Genes, Reporter ; Genetic aspects ; Genomes ; Health aspects ; Hedgehog protein ; Hedgehog proteins ; Hedgehog Proteins - deficiency ; Hedgehog Proteins - genetics ; Hedgehog Proteins - physiology ; Kinases ; Mice ; Mice, Inbred C57BL ; Microcephaly ; Osteogenesis - genetics ; Polydactyly - genetics ; Regulatory Sequences, Nucleic Acid ; Rodents ; Sequence Analysis, DNA ; Sequences ; Skull ; Skull - abnormalities ; Stem cells ; Studies ; Sutures ; Syndactyly ; Transcription, Genetic ; Transgenic
    ISSN: 1061-4036
    E-ISSN: 1546-1718
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: PloS one, 2013, Vol.8 (8), p.e70151-e70151
    Description: The identification of disease-causing mutations in next-generation sequencing (NGS) data requires efficient filtering techniques. In patients with rare recessive diseases, compound heterozygosity of pathogenic mutations is the most likely inheritance model if the parents are non-consanguineous. We developed a web-based compound heterozygous filter that is suited for data from NGS projects and that is easy to use for non-bioinformaticians. We analyzed the power of compound heterozygous mutation filtering by deriving background distributions for healthy individuals from different ethnicities and studied the effectiveness in trios as well as more complex pedigree structures. While usually more then 30 genes harbor potential compound heterozygotes in single exomes, this number can be markedly reduced with every additional member of the pedigree that is included in the analysis. In a real data set with exomes of four family members, two sisters affected by Mabry syndrome and their healthy parents, the disease-causing gene PIGO, which harbors the pathogenic compound heterozygous variants, could be readily identified. Compound heterozygous filtering is an efficient means to reduce the number of candidate mutations in studies aiming at identifying recessive disease genes in non-consanguineous families. A web-server is provided to make this filtering strategy available at www.gene-talk.de.
    Subject(s): Acids ; Analysis ; Bioinformatics ; Biology ; Computational Biology - methods ; Computer Science ; Disease ; Exome - genetics ; Families & family life ; Filtration ; Genes ; Genetic aspects ; Genetics ; Genomes ; Heredity ; Heterozygote ; Heterozygotes ; High-Throughput Nucleotide Sequencing ; Humans ; Medicine ; Mutation ; Parameter estimation ; Parents ; Parents & parenting ; Pedigree
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 8
    Language: English
    In: Nature (London), 2021-04, Vol.592 (7852), p.93
    Description: Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks , but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.
    Subject(s): Animals ; Cell Line ; Chromatin - genetics ; Disease Models, Animal ; Extremities ; Female ; Homeodomain Proteins - genetics ; Humans ; Limb Deformities, Congenital - genetics ; Mice ; Mice, Transgenic ; RNA, Long Noncoding - genetics ; Sequence Deletion - genetics ; Transcription, Genetic ; Transcriptional Activation - genetics
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Get It Now
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  • 9
    Language: English
    In: Bioinformatics, 2017-01-01, Vol.33 (1), p.72-78
    Description: Next generation sequencing technology considerably changed the way we screen for pathogenic mutations in rare Mendelian disorders. However, the identification of the disease-causing mutation amongst thousands of variants of partly unknown relevance is still challenging and efficient techniques that reduce the genomic search space play a decisive role. Often segregation- or linkage analysis are used to prioritize candidates, however, these approaches require correct information about the degree of relationship among the sequenced samples. For quality assurance an automated control of pedigree structures and sample assignment is therefore highly desirable in order to detect label mix-ups that might otherwise corrupt downstream analysis. We developed an algorithm based on likelihood ratios that discriminates between different classes of relationship for an arbitrary number of genotyped samples. By identifying the most likely class we are able to reconstruct entire pedigrees iteratively, even for highly consanguineous families. We tested our approach on exome data of different sequencing studies and achieved high precision for all pedigree predictions. By analyzing the precision for varying degrees of relatedness or inbreeding we could show that a prediction is robust down to magnitudes of a few hundred loci. A java standalone application that computes the relationships between multiple samples as well as a Rscript that visualizes the pedigree information is available for download as well as a web service at www.gene-talk.de CONTACT: heinrich@molgen.mpg.deSupplementary information: Supplementary data are available at Bioinformatics online.
    Subject(s): Algorithms ; Exome ; Female ; Genetic Linkage ; Genome, Human ; Genomics - methods ; High-Throughput Nucleotide Sequencing - methods ; Humans ; Male ; Mutation ; Original Papers ; Pedigree ; Sequence Analysis, DNA - methods ; Software
    ISSN: 1367-4803
    E-ISSN: 1367-4811
    E-ISSN: 1460-2059
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Alma/SFX Local Collection
    Source: Oxford Journals 2016 Current and Archive A-Z Collection
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  • 10
    Language: English
    In: European journal of human genetics : EJHG, 2015-06, Vol.23 (6), p.870-873
    Description: Neurofibromatosis type 1 (NF1) (MIM#162200) is a relatively frequent genetic condition that predisposes to tumor formation. The main types of tumors occurring in NF1 patients are cutaneous and subcutaneous neurofibromas, plexiform neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors. To search for somatic mutations in cutaneous (dermal) neurofibromas, whole-exome sequencing (WES) was performed on seven spatially separated tumors and two reference tissues (blood and unaffected skin) from a single NF1 patient. Validation of WES findings was done using routine Sanger sequencing or Sequenom IPlex SNP genotyping. Exome sequencing confirmed the existence of a known familial splice-site mutation NM_000267.3:c.3113+1G〉A in exon 23 of NF1 gene (HGMD ID CS951480) in blood, unaffected skin, and all tumor samples. In five out of seven analyzed tumors, we additionally detected second-hit mutations in the NF1 gene. Four of them were novel and one was previously observed. Each mutation was distinct, demonstrating the independent origin of each tumor. Only in two of seven tumors we detected an additional somatic mutation that was not associated with NF1. Our study demonstrated that somatic mutations of NF1 are likely the main drivers of cutaneous tumor formation. The study provides evidence for the rareness of single base pair level alterations in the exomes of benign NF1 cutaneous tumors.
    Subject(s): Brain cancer ; Clonal Evolution ; Exome ; Female ; Genes ; Genetics ; Genomes ; Genomics ; Genotyping ; Humans ; Id protein ; Middle Aged ; Mutation ; Neurofibromatosis ; Neurofibromatosis 1 - genetics ; Neurofibromin 1 ; Neurofibromin 1 - genetics ; Patients ; Planck, Max ; Polymorphism, Single Nucleotide ; Proteins ; Recklinghausen's disease ; Short Report ; Single-nucleotide polymorphism ; Skin ; Skin Neoplasms - genetics ; Stem cells ; Tumorigenesis ; Tumors
    ISSN: 1018-4813
    E-ISSN: 1476-5438
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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