Dynamic regulation of stress-responsive non-genomic CTCF complexes [ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA587461 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10398549.fastq.gz | Fastqsanger.gz | |||
| SRR10398550.fastq.gz | Fastqsanger.gz | |||
| SRR10398551.fastq.gz | Fastqsanger.gz | |||
| SRR10398552.fastq.gz | Fastqsanger.gz | |||
| SRR10398553.fastq.gz | Fastqsanger.gz |
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Project description:Dynamic regulation of stress-responsive non-genomic CTCF complexes
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Project description:Dynamic regulation of stress-responsive non-genomic CTCF complexes [RIP-seq]
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Project description: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.
2022-01-19 | GSE139885 | GEO
Project description: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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Project description:While the core members of the Polycomb family of proteins (PRC2, PRC1, PR-DUB) are well-characterized, little is known about the specific composition of and protein-protein interactions within these complexes in different cell types. We performed quantitative interaction proteomics and cross-linking mass spectrometry on core Polycomb complex members to identify novel interactors, the relative abundance (stoichiometry) of subunits, and the architecture of these complexes in mouse embryonic stem cells (mESCs) and neural progenitor cells (NPCs). Differentiation to NPCs resulted in dramatic binding changes for several substoichiometric interactors of PRC2 and PRC1. ChIP-seq of core PRC2 and PRC1 subunits in mESCs and NPCs also identified dynamic changes in the genomic localization of these complexes. We observed a loss of PRC2 from most H3K27me3 sites during differentiation, whereas PRC1 is retained at these sites. Additionally, we found PRC1 at enhancers and promoters of active genes independent of PRC2 binding. Overexpression studies using NPC-specific PRC1 interactors demonstrated that the subunit switching observed during differentiation can change PRC1 target site binding. Altogether, these findings extend our understanding of Polycomb family composition, architecture, and genome-wide localization. ChIP-seq samples for Suz12, Ezh2, Ring1b, Pcgf2, and inputs from mouse embryonic stems cells (mES) and neural progenitor cells (NPC) as well as NPC histone H3K4me1 ChIP-seq.
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Project description:While the core members of the Polycomb family of proteins (PRC2, PRC1, PR-DUB) are well-characterized, little is known about the specific composition of and protein-protein interactions within these complexes in different cell types. We performed quantitative interaction proteomics and cross-linking mass spectrometry on core Polycomb complex members to identify novel interactors, the relative abundance (stoichiometry) of subunits, and the architecture of these complexes in mouse embryonic stem cells (mESCs) and neural progenitor cells (NPCs). Differentiation to NPCs resulted in dramatic binding changes for several substoichiometric interactors of PRC2 and PRC1. ChIP-seq of core PRC2 and PRC1 subunits in mESCs and NPCs also identified dynamic changes in the genomic localization of these complexes. We observed a loss of PRC2 from most H3K27me3 sites during differentiation, whereas PRC1 is retained at these sites. Additionally, we found PRC1 at enhancers and promoters of active genes independent of PRC2 binding. Overexpression studies using NPC-specific PRC1 interactors demonstrated that the subunit switching observed during differentiation can change PRC1 target site binding. Altogether, these findings extend our understanding of Polycomb family composition, architecture, and genome-wide localization.
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