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Long non-coding RNA lnc-TSSK2-8 activates canonical Wnt/β-catenin signaling through small shock proteins HSPA6 and CRYAB

ABSTRACT: Congenital heart defect (CHD) is the most common birth defect worldwide. Copy number variations (CNVs) have been revealed as an important source of pathogenic factor of CHD. 22q11.2 deletion syndrome is the most common microdeletion disorder which has been frequently associated with conotruncal malformations. By now, the dosage sensitive geneTBX1 has been adopted as the major pathogenic gene responsible for 22q11.2 deletion-related heart defects. Here we report the lncRNA lnc-TSSK2-8, which is encompassed in the 22q11.2 region, could activate the canonical Wnt/ -catenin signaling by protecting -catenin from ubiquitination and degradation. Such effects were mediated by two short heat shock proteins HSPA6 and CRYAB, whose expression were regulated by lnc-TSSK2-8 through the ceRNA mechanism. In clinical practice, pathogenesis of CNV were always attributed to haploinsufficiency of protein coding genes. Here we report the 22q11.2 lncRNA lnc-TSSK2-8 significantly activate canonical Wnt/ -catenin signaling, which has major roles in cardiac out flow tract development and should act upstream of TBX1. Our results suggested that lncRNAs should contribute to the etiology of CNV related CHD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165927 | GEO | 2021/06/02

REPOSITORIES: GEO

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A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion

Project description:The 22q11.2 deletion syndrome (22q11.2DS) is the most common copy number variant (CNV)-associated syndrome, leading to congenital and neuropsychiatric anomalies. Patient-derived, induced pluripotent stem cell (iPS) models have provided important insight into the mechanisms of phenotypic features of this condition. However, patient-derived iPSC models may harbor underlying genetic heterogeneity that can confound analysis of pathogenic CNV effects. Furthermore, the ~1.5 Mb “A-B” deletion at this locus is inherited at higher frequency than the more common ~2.7 Mb “A-D” deletion, but remains under-studied due to lack of relevant models. To address these issues, here we leveraged a CRISPR-based strategy in Cas9-expressing iPS cells to engineer novel isogenic models of the 22q11.2 “A-B” deletion. After in vitro differentiation to excitatory neurons, integrated transcriptomic and cell surface proteomics identified deletion-associated alterations in surface adhesion markers. Furthermore, implantation of iPS-derived neuronal progenitor cells into the cortex of neonatal mice found decreased proliferation and accelerated neuronal maturation within a relevant microenvironment. Taken together, our results suggest potential pathogenic mechanisms of the 22q11.2 “A-B” deletion in driving neuronal and neurodevelopmental phenotypes. We further propose that the isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.

2023-05-11 | PXD032075 | Pride

Long non-coding RNA lnc-TSSK2-8 activates canonical Wnt/β-catenin signaling through small shock proteins HSPA6 and CRYAB

Project description:Long non-coding RNA lnc-TSSK2-8 activates canonical Wnt/β-catenin signaling through small shock proteins HSPA6 and CRYAB

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lnc-EAPV binding proteins in C57BL/6J BMDMs

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2018-11-07 | PXD011577 | Pride

Reduced dosage of Î²-catenin genetically rescues intracardiac anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome

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2016-09-01 | E-GEOD-78125 | biostudies-arrayexpress

Rare de novo copy number variants in patients with congenital pulmonary atresia

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2014-04-02 | E-GEOD-56422 | biostudies-arrayexpress

A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion

Project description:The 22q11.2 deletion syndrome (22q11.2DS) is the most common copy number variant (CNV)-associated syndrome, leading to congenital, cognitive, and neuropsychiatric anomalies in patients. The clinical presentation of the disease phenotypes is variable, posing significant challenges for prognosis of inheritance risk and clinical outcomes for the CNV carriers. ~85% of patients and almost all available human-centered models of this condition reflect the ~2.7 Mb “A-D” deletion at this locus. Leveraging a CRISPR/Cas9-based engineering strategy and induced pluripotent stems cells, we generated novel isogenic models for the smaller, commonly inherited 1.5 Mb “A-B” deletion found in ~5-10% of 22q11.2DS patients. The bulk RNA-seq data included here reflects paired-end 100 bp sequencing of iPSC-derived neuronal progenitor cells and excitatory neurons. These data reflect three independent clones either carrying the designed 22q11.2 deletion or control comparators (2 clones nucleofected with same sgRNA but with no deletion generated; 1 clone derived from the parental Cas9-expressing iPSC line). We anticipate that these novel, isogenic models will carry significant utility for the study of 22q11.2 deletion syndrome.

2022-05-02 | GSE200225 | GEO

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Project description:The most common congenital heart disease (CHD) is the ventricular septal defect (VSD), which is also a subfeature of Tetralogy of Fallot (TOF) representing the most common form of cyanotic CHD. The underlying causes for the majority of CHDs are still unclear and most probably consist of combinations of genetic, epigenetic and environmental factors. DNA methylation is the most widely studied epigenetic modification and several cardiac regulators have already been shown to be differentially methylated in CHD patients. Here, we present the first analysis of genome-wide DNA methylation data obtained from cardiac biopsies of TOF and VSD patients. We applied affinity-based enrichment of methylated DNA sequences with methyl-CpG-binding domain proteins followed by next-generation sequencing (MBD-Seq). MBD-seq on cardiac biopsies of patients with Tetralogy of Fallot and ventricular septal defect

2016-08-08 | E-GEOD-62629 | biostudies-arrayexpress

Array CGH in congenital heart disease

Project description:Congenital heart disease (CHD) is the most frequent birth defect and affects nearly 1% of newborns. The etiology of CHD is largely unknown and only a small percentage can be assigned to environmental risk factors such as maternal diseases or exposure to mutagenic agents during pregnancy. Chromosomal imbalances have been identified in many forms of syndromic CHD, but next to nothing is known about the impact of DNA copy number changes in non-syndromic CHD. Here we present a sub-megabase resolution array CGH screen of a cohort with CHD as the sole abnormality at the time of diagnosis. Keywords: array CGH In this BAC array CGH study 104 patients with congenital heart disease and some of their parents were screened for DNA copy number changes at submegabase resolution. No dye swap was performed.

2008-05-11 | E-GEOD-7527 | biostudies-arrayexpress

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

Project description:Here we aimed to contribute to the description of the genetic architecture of Congenital heart defect (CHD) in Down syndrome (DS), and report the results of a genome-wide association study using samples from DS individuals with and without CHD. CHD is a common developmental defect of DS occurring in 40% of cases. This case-control GWAS includes 187 DS with CHD as cases, and 151 DS without CHD as controls.

| EGAS00000000129 | EGA

Array CGH in congenital heart disease

2008-05-12 | GSE7527 | GEO

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