Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer

被引：0
作者：
Kakani, Parik [1 ]
Dhamdhere, Shruti Ganesh [1 ]
Pant, Deepak [1 ]
Joshi, Rushikesh [1 ,3 ]
Mishra, Sachin [2 ,4 ]
Pandey, Anchala [1 ]
Notani, Dimple [2 ]
Shukla, Sanjeev [1 ]
机构：
[1] Indian Inst Sci Educ & Res Bhopal, Dept Biol Sci, Bhopal 462066, Madhya Pradesh, India
[2] Tata Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore 560065, Karnataka, India
[3] CSIR Inst Genom & Integrat Biol CSIR IGIB, New Delhi 110025, India
[4] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Vienna, Austria
来源：
CELL REPORTS | 2025年 / 44卷 / 02期
关键词：
TO-MESENCHYMAL TRANSITION; DNA METHYLATION; TUMOR; DATABASE; BINDING; METASTASIS; SIGNATURES; EXPANSION; ROBUST; SITES;
D O I：
10.1016/j.celrep.2025.115267
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
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 (HIF1a), 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 HIF1a-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.
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页数：26
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