
@article {154146,
	title = {Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer.},
	journal = {Cell Rep},
	volume = {44},
	year = {2025},
	month = {2025 Feb 04},
	pages = {115267},
	abstract = {<p>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.</p>
},
	keywords = {COL5A1; CP: Cancer; CP: Molecular biology; CRISPR-dCas9-mediated editing; CTCF; EMT; alternative splicing; breast cancer; epigenetics; hypoxia; promoter-exon upstream looping.},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2025.115267},
	url = {https://pubmed.ncbi.nlm.nih.gov/39913285/},
	author = {Kakani, Parik and Dhamdhere, Shruti Ganesh and Pant, Deepak and Joshi, Rushikesh and Mishra, Sachin and Pandey, Anchala and Notani, Dimple and Shukla, Sanjeev}
}
