Dysregulation of gene expression as a cause of cockayne syndrome neurological disease
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Dysregulation of gene expression as a cause of cockayne syndrome neurological disease. / Wang, Yuming; Chakravarty, Probir; Ranes, Michael; Kelly, Gavin; Brooks, Philip J.; Neilan, Edward; Stewart, Aengus; Schiavo, Giampietro; Svejstrup, Jesper Q.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 111, Nr. 40, 2014, s. 14454-14459.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Dysregulation of gene expression as a cause of cockayne syndrome neurological disease
AU - Wang, Yuming
AU - Chakravarty, Probir
AU - Ranes, Michael
AU - Kelly, Gavin
AU - Brooks, Philip J.
AU - Neilan, Edward
AU - Stewart, Aengus
AU - Schiavo, Giampietro
AU - Svejstrup, Jesper Q.
PY - 2014
Y1 - 2014
N2 - 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 neuntes. 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.
AB - 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 neuntes. 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.
KW - CSA
KW - Gene regulation
KW - Neuritogenesis
KW - Neurology
KW - Reprogramming
U2 - 10.1073/pnas.1412569111
DO - 10.1073/pnas.1412569111
M3 - Journal article
C2 - 25249633
AN - SCOPUS:84907779367
VL - 111
SP - 14454
EP - 14459
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 40
ER -
ID: 330898655