Dysregulation of gene expression as a cause of Cockayne syndrome neurological disease

Significance

Cockayne syndrome (CS) is an autosomal-recessive, multisystem disorder characterized by neurological disease, growth failure, developmental abnormalities, photosensitivity, and degeneration of organ systems such as the ear and eye, including cataracts. Most patients with CS carry mutations in Cockayne syndrome group B (CSB), best known for its role in transcription-coupled repair. Indeed, because various repair pathways are compromised in patient cells, CS is widely considered a genome instability syndrome. Here, we provide evidence from human and mouse cell models, as well as brain tissue from patients with CS, that the involvement of CSB in regulating gene expression can explain several features of CS. Together, our data suggest that dysregulation of gene regulatory networks rather than DNA repair defects may be the main cause of neurological symptoms in CS.

Abstract

Cockayne syndrome (CS) is a multisystem disorder with severe neurological symptoms. The majority of CS patients carry mutations in Cockayne syndrome group B (CSB), best known for its role in transcription-coupled nucleotide excision repair. Indeed, because various repair pathways are compromised in patient cells, CS is widely considered a genome instability syndrome. Here, we investigate the connection between the neuropathology of CS and dysregulation of gene expression. Transcriptome analysis of human fibroblasts revealed that even in the absence of DNA damage, CSB affects the expression of thousands of genes, many of which are neuronal genes. CSB is present in a significant subset of these genes, suggesting that regulation is direct, at the level of transcription. Importantly, reprogramming of CS fibroblasts to neuron-like cells is defective unless an exogenous CSB gene is introduced. Moreover, neuroblastoma cells from which CSB is depleted show defects in gene expression programs required for neuronal differentiation, and fail to differentiate and extend neurites. Likewise, neuron-like cells cannot be maintained without CSB. Finally, a number of disease symptoms may be explained by marked gene expression changes in the brain of patients with CS. Together, these data point to dysregulation of gene regulatory networks as a cause of the neurological symptoms in CS.