title: Dysregulation of gene expression as a cause of Cockayne syndrome neurological disease.
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.
authors.affiliation: Mechanisms of Transcription Laboratory, Cancer Research UK London Research Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Yuming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Bioinformatics and Biostatistics Group, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravarty
authors.affiliation: Mechanisms of Transcription Laboratory, Cancer Research UK London Research Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Michael
authors.initials: M
authors.lastname: Ranes
authors.affiliation: Bioinformatics and Biostatistics Group, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelly
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism and Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Brooks
authors.affiliation: Genetics and Metabolism, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Edward
authors.initials: E
authors.lastname: Neilan
authors.affiliation: Bioinformatics and Biostatistics Group, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
authors.forename: Aengus
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
authors.affiliation: Mechanisms of Transcription Laboratory, Cancer Research UK London Research Institute, South Mimms EN6 3LD, United Kingdom; jesper.svejstrup@cancer.org.uk.
authors.forename: Jesper Q
authors.initials: JQ
authors.lastname: Svejstrup
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000235:genetics; D002478:Cells, Cultured; D003057:Cockayne Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000075223:Poly-ADP-Ribose Binding Proteins; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes
keywords: CSA; gene regulation; neuritogenesis; neurology; reprogramming