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| Status |
Public on Sep 09, 2013 |
| Title |
Lamin B1 depletion in senescent cells triggers large-Scale changes in gene expression and in the chromatin landscape[ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Cellular senescence is a stable proliferation arrest in response to stress, associated with an altered secretory pathway (Senescence Associated Secretory Phenotype (SASP)). Senescence-associated proliferation arrest and the SASP are thought to act in concert to promote tumor suppression and tissue aging. While chromatin regulation and down regulation of lamin B1 have been implicated as effectors of cell senescence, functional interactions between them are poorly understood. We compared the genome-wide distributions of H3K4me3 and H3K27me3 between proliferating and senescent primary human cells and found dramatic differences, including large-scale domains of H3K4me3- and H3K27me3-enriched "mesas" and H3K27me3-depleted "canyons" in senescent cells. Senescent mesas form at the sites of lamin B1-associated domains (LADs) in proliferating cells. Mesas also overlap with regions that exhibit DNA hypomethylation in cancer, suggesting that chromatin changes in pre-malignant senescent cells foreshadow epigenetic changes in cancer. Proliferating fibroblasts from Hutchinson-Gilford Progeria Syndrome patients expressing mutant lamin A (progerin) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence and tissue aging. In contrast, canyons form mostly in between LADs and are enriched in genes, gene promoters and enhancers. Strikingly, H3K27me3 loss in canyons is correlated with upregulation of key senescence genes, including genes comprising the SASP, indicating a link between global changes in chromatin structure and local regulation of gene expression. Finally, premature reduction of lamin B1 in midlife proliferating cells triggers formation of senescence-associated mesas and canyons and accelerated senescence. Together, our data illustrate a profound reorganization of chromatin during senescence, and suggest that down regulation of lamin B1 in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging and cancer.
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| Overall design |
One lane per sample, with replicates; four lanes H3 (one proliferating, one senescent, one control, one Ras-induced), four lanes H3K27me3 (three proliferating, one senescent), two lanes H3K4me3 (one control, one ras-induced)
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| Contributor(s) |
Shah PP, Donahue G, Otte G, Capell B, Nelson DM, Cao K, Aggarwala V, Cruickshanks H, Rai TS, McBryan T, Gregory B, Sandhu D, Adams PD, Berger SL |
| Citation(s) |
23934658 |
| Submission date |
Mar 19, 2012 |
| Last update date |
May 15, 2019 |
| Contact name |
Gregory Donahue |
| Organization name |
The University of Pennsylvania
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| Department |
Cell & Developmental Biology
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| Lab |
Zaret Lab
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| Street address |
3400 Civic Center Blvd, Bldg 421
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (2) |
| GPL10999 |
Illumina Genome Analyzer IIx (Homo sapiens) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (17)
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| This SubSeries is part of SuperSeries: |
| GSE36641 |
Lamin B1 depletion in senescent cells leads to large-scale changes in the chromatin landscape |
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| Relations |
| SRA |
SRP011584 |
| BioProject |
PRJNA155425 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE36616_H3K27me3_canyons.bed.gz |
11.3 Kb |
(ftp)(http) |
BED |
| GSE36616_H3K27me3_mesas.bed.gz |
11.9 Kb |
(ftp)(http) |
BED |
| GSE36616_H3K4me3_OIS_mesas.bed.gz |
6.3 Kb |
(ftp)(http) |
BED |
| GSE36616_H3K4me3_mesas.bed.gz |
5.1 Kb |
(ftp)(http) |
BED |
| GSE36616_LADs.bed.gz |
14.2 Kb |
(ftp)(http) |
BED |
| GSE36616_RAW.tar |
2.9 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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