Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer
Summary: Hypoxia influences the epithelial-mesenchymal transition (EMT) through the remodeling of the chromatin structure, epigenetics, and alternative splicing. Hypoxia drives CCCTC-binding factor (CTCF) induction through hypoxia-inducible factor 1-alpha (HIF1α), which promotes EMT, although the un...
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Elsevier
2025-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000385 |
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| author | Parik Kakani Shruti Ganesh Dhamdhere Deepak Pant Rushikesh Joshi Sachin Mishra Anchala Pandey Dimple Notani Sanjeev Shukla |
| author_facet | Parik Kakani Shruti Ganesh Dhamdhere Deepak Pant Rushikesh Joshi Sachin Mishra Anchala Pandey Dimple Notani Sanjeev Shukla |
| author_sort | Parik Kakani |
| collection | DOAJ |
| description | Summary: Hypoxia influences the epithelial-mesenchymal transition (EMT) through the remodeling of the chromatin structure, epigenetics, and alternative splicing. Hypoxia drives CCCTC-binding factor (CTCF) induction through hypoxia-inducible factor 1-alpha (HIF1α), which promotes EMT, although the underlying mechanisms remain unclear. We find that hypoxia significantly increases CTCF occupancy at various EMT-related genes. We present a CTCF-mediated intricate mechanism promoting EMT wherein CTCF binding at the collagen type V alpha 1 chain (COL5A1) promoter is crucial for COL5A1 upregulation under hypoxia. Additionally, hypoxia drives exon64A inclusion in a mutually exclusive alternative splicing event of COL5A1exon64 (exon64A/64B). Notably, CTCF mediates COL5A1 promoter-alternatively spliced exon upstream looping that regulates DNA demethylation at distal exon64A. This further regulates the CTCF-mediated RNA polymerase II pause at COL5A1exon64A, leading to its inclusion in promoting the EMT under hypoxia. Genome-wide study indicates the association of gained CTCF occupancy with the alternative splicing of many cancer-related genes, similar to the proposed model. Specifically, disrupting the HIF1α-CTCF-COL5A1exon64A axis through the dCas9-DNMT3A system alleviates the EMT in hypoxic cancer cells and may represent a novel therapeutic target in breast cancer. |
| format | Article |
| id | doaj-art-b8d3c2c9cc0a48b8940d4b5d75c089e5 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-b8d3c2c9cc0a48b8940d4b5d75c089e52025-02-06T05:11:31ZengElsevierCell Reports2211-12472025-02-01442115267Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancerParik Kakani0Shruti Ganesh Dhamdhere1Deepak Pant2Rushikesh Joshi3Sachin Mishra4Anchala Pandey5Dimple Notani6Sanjeev Shukla7Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, IndiaDepartment of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, IndiaDepartment of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, IndiaDepartment of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, IndiaNational Center for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, Karnataka 560065, IndiaDepartment of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, IndiaNational Center for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, Karnataka 560065, IndiaDepartment of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, India; Corresponding authorSummary: Hypoxia influences the epithelial-mesenchymal transition (EMT) through the remodeling of the chromatin structure, epigenetics, and alternative splicing. Hypoxia drives CCCTC-binding factor (CTCF) induction through hypoxia-inducible factor 1-alpha (HIF1α), which promotes EMT, although the underlying mechanisms remain unclear. We find that hypoxia significantly increases CTCF occupancy at various EMT-related genes. We present a CTCF-mediated intricate mechanism promoting EMT wherein CTCF binding at the collagen type V alpha 1 chain (COL5A1) promoter is crucial for COL5A1 upregulation under hypoxia. Additionally, hypoxia drives exon64A inclusion in a mutually exclusive alternative splicing event of COL5A1exon64 (exon64A/64B). Notably, CTCF mediates COL5A1 promoter-alternatively spliced exon upstream looping that regulates DNA demethylation at distal exon64A. This further regulates the CTCF-mediated RNA polymerase II pause at COL5A1exon64A, leading to its inclusion in promoting the EMT under hypoxia. Genome-wide study indicates the association of gained CTCF occupancy with the alternative splicing of many cancer-related genes, similar to the proposed model. Specifically, disrupting the HIF1α-CTCF-COL5A1exon64A axis through the dCas9-DNMT3A system alleviates the EMT in hypoxic cancer cells and may represent a novel therapeutic target in breast cancer.http://www.sciencedirect.com/science/article/pii/S2211124725000385CP: CancerCP: Molecular biology |
| spellingShingle | Parik Kakani Shruti Ganesh Dhamdhere Deepak Pant Rushikesh Joshi Sachin Mishra Anchala Pandey Dimple Notani Sanjeev Shukla Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer Cell Reports CP: Cancer CP: Molecular biology |
| title | Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer |
| title_full | Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer |
| title_fullStr | Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer |
| title_full_unstemmed | Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer |
| title_short | Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer |
| title_sort | hypoxia induced ctcf mediates alternative splicing via coupling chromatin looping and rna pol ii pause to promote emt in breast cancer |
| topic | CP: Cancer CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725000385 |
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