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Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE116794 | GEO | 2018/11/19

REPOSITORIES: GEO

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Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [RNA-Seq]

Project description:Here we study the effect of balanced chromosomal rearrangements (BCRs) on gene expression in vivo in mouse embryos by generating a series of genomic inversions that place an active enhancer cluster located in the Epha4 regulatory domain at different positions within a neighboring gene dense region. Expression studies in embryonic limb buds show that the inverted enhancer cluster was able to activate several genes downstream of its new position, resulting in gene misexpression and limb phenotypes. Capture Hi-C from mutant limb buds showed that the activated genes were located within a region of asymmetric three-dimensional contacts, so called architectural stripes. Deletion of the CTCF binding site at that position of the stripe anchor resulted in a collapse of the stripes, down regulation of ectopic gene expression, and a rescue of the skeletal phenotype. In cells in which the enhancers are not active, such as mouse embryonic stem cells (mESCs), stripes do not form, indicating that their formation is also dependent on enhancer activity. Based on HiC from limb buds we show that architectural stripes are a frequent feature in the genome often associated with developmentally active enhancers. Thus, BCRs can induce ectopic gene expression via the formation of asymmetric chromatin contacts. The formation of these stripes is dependent on CTCF anchors and enhancer activity.

2018-11-19 | GSE116793 | GEO

Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [cHi-C]

2018-11-19 | GSE116792 | GEO

Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [Hi-C]

2018-11-19 | GSE116791 | GEO

Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [ChIP-seq]

2018-11-19 | GSE116790 | GEO

Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations

Project description:Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations

| PRJNA480261 | ENA

Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [ChIP-seq]

Project description:Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [ChIP-seq]

| PRJNA480256 | ENA

Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [cHi-C]

Project description:Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [cHi-C]

| PRJNA480257 | ENA

Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [Hi-C]

Project description:Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [Hi-C]

| PRJNA480258 | ENA

Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [RNA-Seq]

Project description:Serial Inversions Induce Tissue-specific Architectural Stripes, Gene Misexpression and Congenital Malformations [RNA-Seq]

| PRJNA480259 | ENA

Increased <i>TBX6</i> gene dosages induce congenital cervical vertebral malformations in humans and mice.

Project description:BackgroundCongenital vertebral malformations (CVMs) manifest with abnormal vertebral morphology. Genetic factors have been implicated in CVM pathogenesis, but the underlying pathogenic mechanisms remain unclear in most subjects. We previously reported that the human 16p11.2 BP4-BP5 deletion and its associated TBX6 dosage reduction caused CVMs. We aim to investigate the reciprocal 16p11.2 BP4-BP5 duplication and its potential genetic contributions to CVMs.Methods and resultsPatients who were found to carry the 16p11.2 BP4-BP5 duplication by chromosomal microarray analysis were retrospectively analysed for their vertebral phenotypes. The spinal assessments in seven duplication carriers showed that four (57%) presented characteristics of CVMs, supporting the contention that increased TBX6 dosage could induce CVMs. For further in vivo functional investigation in a model organism, we conducted genome editing of the upstream regulatory region of mouse Tbx6 using CRISPR-Cas9 and obtained three mouse mutant alleles (Tbx6up1 to Tbx6up3 ) with elevated expression levels of Tbx6. Luciferase reporter assays showed that the Tbx6up3 allele presented with the 160% expression level of that observed in the reference (+) allele. Therefore, the homozygous Tbx6up3/up3 mice could functionally mimic the TBX6 dosage of heterozygous carriers of 16p11.2 BP4-BP5 duplication (approximately 150%, ie, 3/2 gene dosage of the normal level). Remarkably, 60% of the Tbx6up3/up3 mice manifested with CVMs. Consistent with our observations in humans, the CVMs induced by increased Tbx6 dosage in mice mainly affected the cervical vertebrae.ConclusionOur findings in humans and mice consistently support that an increased TBX6 dosage contributes to the risk of developing cervical CVMs.

| S-EPMC9179029 | biostudies-literature

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