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| Status |
Public on Jan 19, 2022 |
| Title |
Dynamic regulation of stress-responsive non-genomic CTCF complexes [RIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The nuclear protein CCCTC-binding factor (CTCF) has diverse roles in chromatin architecture and gene regulation. Functionally, CTCF associates with thousands of genomic sites and interacts with proteins, such as cohesin, or non-coding RNAs to facilitate specific transcriptional programming. In this study, we examined CTCF during the cellular stress response in human primary cells using immune-blotting, quantitative real time-PCR, chromatin immunoprecipitation-sequence analysis, mass spectrometry, RNA immunoprecipitation-sequence analysis, and Airyscan confocal microscopy. Unexpectedly, we found that CTCF is exquisitely sensitive to diverse forms of stress in normal patient-derived human mammary epithelial cells (HMECs). In HMECs, the majority of CTCF protein forms non-genomic complexes that localize to Serine/arginine-rich splicing factor (SC-35)-containing nuclear speckles, exclusive of its canonical association with chromatin. Upon stress, non-genomic CTCF protein is rapidly downregulated by changes in protein stability, resulting in loss of CTCF from SC-35 nuclear speckles and changes in CTCF-RNA interactions. CTCF complexes that associate with genomic DNA are resistant to stress-induced degradation and CTCF-DNA binding is largely unchanged. Restoration of cellular CTCF protein abundance and re-localization to nuclear speckles can be achieved by inhibition of proteasome-mediated degradation. Surprisingly, we observed the same characteristics of the stress response during neuronal differentiation of human pluripotent stem cells (hPSC). CTCF forms stress-sensitive complexes that localize to SC-35 nuclear speckles during a specific stage of neuronal commitment/development but not in differentiated neurons. We speculate that these non-canonical CTCF complexes serve a largely non-genomic role in RNA processing, potentially to maintain cells in a particular differentiation state, that is dynamically regulated by environmental signals. The non-canonical, stress-regulated activity of CTCF is uncoupled in persistently stressed, epigenetically re-programmed “variant” HMECs and certain cancer cell lines. These results reveal new insights into CTCF function in cell differentiation and the stress-response with implications for oxidative damage-induced cancer initiation and neuro-degenerative diseases.
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| Overall design |
RIP-Seq
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| Contributor(s) |
Lehman BJ, Lopez-Diaz FJ, Santisakultarm TP, Fang L, Shokhirev MN, Diffenderfer KE, Manor U, Emerson BM |
| Citation(s) |
33411704 |
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| Submission date |
Nov 04, 2019 |
| Last update date |
Mar 28, 2022 |
| Contact name |
April Elizabeth Williams |
| E-mail(s) |
apriljack06@gmail.com, awilliams@salk.edu
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| Phone |
7345461645
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| Organization name |
Salk Institute for Biological Studies
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| Department |
IGC
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| Street address |
10010 N Torrey Pines Rd
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| City |
San Diego |
| State/province |
California |
| ZIP/Postal code |
92037 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE139886 |
Dynamic regulation of stress-responsive non-genomic CTCF complexes |
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| Relations |
| BioProject |
PRJNA587478 |
| SRA |
SRP228542 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE139885_diff.Down_input_hmec_vs_ctcf_hmec.txt.gz |
97.0 Kb |
(ftp)(http) |
TXT |
| GSE139885_diff.Down_input_vhmec_vs_ctcf_vhmec.txt.gz |
93.0 Kb |
(ftp)(http) |
TXT |
| GSE139885_diff.Up_sc35_hmec_vs_input_hmec.txt.gz |
315.9 Kb |
(ftp)(http) |
TXT |
| GSE139885_diff.Up_sc35_vhmec_vs_input_vhmec.txt.gz |
351.6 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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