|
| Status |
Public on Jul 29, 2024 |
| Title |
Neurological Cockayne Syndrome Results from R-Loops Induced by Stalled RNA Polymerase II during Transcription Elongation |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Other
Expression profiling by high throughput sequencing
|
| Summary |
Mutations in the Cockayne Syndrome group B (CSB) gene cause severe neurodevelopmental defects and premature aging. As a member of the SWI/SNF family of chromatin remodelers, CSB is best known for its role in transcription-coupled nucleotide excision (TC-NER), but this function neither explains the major disease phenotype nor offers any clue about the selective vulnerability in neurons. Pursuing Cockayne Syndrome-associated genome instability, we uncover an intrinsic mechanism by which elongating RNA polymerase II (RNAPII) undergoes transient pausing at internal T-runs where CSB is required to push RNAPII forward. Consequently, CSB deficiency retards RNAPII elongation in these regions, and when coupled upstream G-rich sequences, such functional defects are further amplified to induce genome instability via augmented R-loop formation. As such R-loop prone motifs are proportionally represented in long genes that predominately function in neurons, this mechanism provides critical insights into selective neuronal vulnerability. Moreover, because of divergent intronic sequences between mice and humans, this mechanism also explains why mice deficient for CSB do not develop severe neurological abnormalities as seen in humans, suggesting that the manifestation of Cockayne Syndrome phenotype results from progressive genome evolution in mammals.
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| Overall design |
To examine the genome instability induced by CSB-deficiency, we performed R-ChIP, PolII ChIP-seq, PRO-seq and chromatin associated RNA-seq under siNC and siCSB condition. Besides, We also performed the CSB ChIP-seq to identify the CSB binding site. All data have two replicates and controls.
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| Web link |
https://www.nature.com/articles/s41467-024-50298-w
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| |
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| Contributor(s) |
Zhang X, Fu X |
| Citation(s) |
39019869 |
| |
| Submission date |
Feb 27, 2023 |
| Last update date |
Aug 05, 2024 |
| Contact name |
Xiang-Dong Fu |
| E-mail(s) |
fuxiangdong@westlake.edu.cn
|
| Organization name |
Westlake University
|
| Street address |
18 Shilongshan Rd.,Cloud Town, Xihu District
|
| City |
Hangzhou |
| State/province |
Zhejiang |
| ZIP/Postal code |
310024 |
| Country |
China |
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| Platforms (5)
|
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
| GPL28038 |
DNBSEQ-G400 (Homo sapiens) |
|
| Samples (37)
|
|
| Relations |
| BioProject |
PRJNA939159 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE226204_CSB_ChIP_peaks.narrowPeak.gz |
17.1 Kb |
(ftp)(http) |
NARROWPEAK |
| GSE226204_HDF_RNA_counts.txt.gz |
4.7 Mb |
(ftp)(http) |
TXT |
| GSE226204_N2A_RNA_counts.txt.gz |
333.8 Kb |
(ftp)(http) |
TXT |
| GSE226204_PRO_siCSB_fwd.bw |
393.9 Mb |
(ftp)(http) |
BW |
| GSE226204_PRO_siCSB_rev.bw |
413.0 Mb |
(ftp)(http) |
BW |
| GSE226204_PRO_siNC_fwd.bw |
347.9 Mb |
(ftp)(http) |
BW |
| GSE226204_PRO_siNC_rev.bw |
364.8 Mb |
(ftp)(http) |
BW |
| GSE226204_PolII_ChIP_siCSB_peaks.narrowPeak.gz |
408.4 Kb |
(ftp)(http) |
NARROWPEAK |
| GSE226204_PolII_ChIP_siNC_peaks.narrowPeak.gz |
306.5 Kb |
(ftp)(http) |
NARROWPEAK |
| GSE226204_RChIP_siCSB.fwd.bed.gz |
60.4 Kb |
(ftp)(http) |
BED |
| GSE226204_RChIP_siCSB.rev.bed.gz |
62.2 Kb |
(ftp)(http) |
BED |
| GSE226204_RChIP_siNC.fwd.bed.gz |
21.3 Kb |
(ftp)(http) |
BED |
| GSE226204_RChIP_siNC.rev.bed.gz |
23.1 Kb |
(ftp)(http) |
BED |
| GSE226204_SHSY5Y_RNA_counts.txt.gz |
362.4 Kb |
(ftp)(http) |
TXT |
| GSE226204_chr_RNA_featureCounts.txt.gz |
4.7 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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