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Abstract
Cockayne syndrome is an inherited premature aging disease associated with numerous developmental and neurological defects, and mutations in the gene encoding the CSB protein account for the majority of Cockayne syndrome cases. Accumulating evidence suggests that CSB functions in transcription regulation, in addition to its roles in DNA repair, and those defects in this transcriptional activity might contribute to the clinical features of Cockayne syndrome. Transcription profiling studies have so far uncovered CSB-dependent effects on gene expression; however, the direct targets of CSB's transcriptional activity remain largely unknown. In this paper, we report the first comprehensive analysis of CSB genomic occupancy during replicative cell growth. We found that CSB occupancy sites display a high correlation to regions with epigenetic features of promoters and enhancers. Furthermore, we found that CSB occupancy is enriched at sites containing the TPA-response element. Consistent with this binding site preference, we show that CSB and the transcription factor c-Jun can be found in the same protein-DNA complex, suggesting that c-Jun can target CSB to specific genomic regions. In support of this notion, we observed decreased CSB occupancy of TPA-response elements when c-Jun levels were diminished. By modulating CSB abundance, we found that CSB can influence the expression of nearby genes and impact nucleosome positioning in the vicinity of its binding site. These results indicate that CSB can be targeted to specific genomic loci by sequence-specific transcription factors to regulate transcription and local chromatin structure. Additionally, comparison of CSB occupancy sites with the MSigDB Pathways database suggests that CSB might function in peroxisome proliferation, EGF receptor transactivation, G protein signaling and NF-κB activation, shedding new light on the possible causes and mechanisms of Cockayne syndrome.
Highlights
Cockayne syndrome is a devastating inherited disease in which patients have features of premature aging, display increased sun sensitivity, and suffer from profound neurological and developmental defects [1]
CSBDN1 or harboring an empty vector (CS1AN)-sv cells that were reconstituted with CSB were used for these experiments, as CS1AN-sv cells do not express the alternatively spliced CSBPiggyBac fusion protein (Figure S1) [30]; this cell line is hemizygous for the CSB locus and the retained CSB allele has a premature stop codon at amino acid 337 [19]
When we compared the CSB occupancy data with those transcription profiling data (Tables 6 and S4), we found that 22% of the genes up-regulated and 30% of genes down-regulated by co-expression of CSB and CSB-PDGB3 were associated with CSB occupancy, and 19% of the genes up-regulated by CSB-PGBD3 alone and 30% of the genes down-regulated by CSB-PGBD3 alone were associated with CSB occupancy
Summary
Cockayne syndrome is a devastating inherited disease in which patients have features of premature aging, display increased sun sensitivity, and suffer from profound neurological and developmental defects [1]. CSB belongs to the SWI2/SNF2 ATP-dependent chromatin remodeling protein family [2]. ATP-dependent chromatin remodelers are conserved from yeast to human, and they are critical in regulating fundamental nuclear processes, such as transcription and DNA repair [3,4]. These proteins use ATP as energy to alter chromatin structure non-covalently, resulting in changes in nucleosome position, composition or conformation. ATPdependent chromatin remodelers can regulate the access of protein factors to DNA. Some SWI2/SNF2 family members can alter contacts between DNA and non-histone proteins [9]. The MOT1 remodeler can use the energy from ATP hydrolysis to dissociate TBP (TATA box binding protein) from DNA [9]
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