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Impaired Endothelial Cell Type Specification and Vascular Function in Cockayne Syndrome B

ABSTRACT: Cockayne Syndrome B (CSB) is a rare genetic disorder caused by mutations in ERCC6, which encodes the DNA excision repair protein Cockayne Syndrome B. Despite numerous multisystem pathologies documented in patients with CSB, little is known about the effects of this disease on vasculature at the cellular level. Using patient-derived stem cells, we investigated how CSB-mediated abnormalities in vascular endothelial cell (vEC) structure negatively impacts function. Compared to wild-type controls, CSB-derived vECs exhibited abnormal morphology and impaired cell-type specification reminiscent of endothelial to mesenchymal transition (EndoMT). CSB-derived vECs also showed reduced proliferated capacity and priming of apoptosis, which was exacerbated upon UV-induced DNA damage. CSB-derived vECs spontaneously formed fewer and thicker vascular tubes and their monolayers exhibited compromised barrier integrity with high permeability. Transcriptomic analysis revealed mechanosensory dysfunction, marked by premature entry into quiescence, dysregulated angiogenic signaling, and maladaptive vasoregulation, which may explain why when under shear stress, CSB vECs exhibited enhanced (and not reduced) adhesion to laminin and fibronectin. Together, these results elucidate the vascular endothelial cell abnormalities that may contribute to vascular dysfunction and pathophysiology of Cockayne Syndrome B.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307216 | GEO | 2026/09/04

REPOSITORIES: GEO

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Project description:Cockayne syndrome is an inherited premature aging syndrome associated with developmental and neurological disorders. Mutations in the genomic locus encoding CSB are associated with 80% Cockayne syndrome cases. Transcription profiling assays reveal the association of mis-regulation of gene expression with Cockayne syndrome, highlighting the importance of CSB in transcription regulation. However, many questions remain unanswered as how CSB regulates transcription. In this study, we dissect the mechanisms by which CSB regulates transcription during normal growth. By anti-CSB chromatin immunoprecipitation followed by deep sequencing, we found CSB is enriched at genomic regions containing TGASTCA motifs, to which the immediate early gene product C-Jun binds specifically. We further demonstrate that c-Jun co-immunoprecipitates with CSB. In addition, the targeting of CSB to genomic region containing TGASTCA motifs was drastically reduced in cells treated c-Jun shRNA. Reverse transcription followed by quantitative PCR indicates that CSB can regulate gene expression nearby its binding sites, both in activation and repression. The remodeling defective CSBM-bM-^HM-^FN1 mutant is also targeted to TGASTCA motifs, but cannot always substitute CSB function in transcription regulating, suggesting the importance of remodeling by CSB in transcription regulation. Notably, the Cockayne syndrome related mutation encoding protein CSBR670W, which is defective in ATP hydrolysis but is targeted to TGASTCA motifs efficiently, indicating that ATP hydrolysis is dispensable for c-Jun mediated CSB targeting, in sharp contrast to the ATP-dependent targeting mechanism by which CSB is relocated to DNA lesion stalled transcription. Together, these results reveal a second CSB targeting mechanism in which DNA sequence specific transcription factor c-Jun targets CSB to specific genomic region and regulate gene expression. Genomic localization of CSB and remodeling deficient CSBM-bM-^HM-^FN1

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Impaired Endothelial Cell Type Specification and Vascular Function in Cockayne Syndrome B

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