Year: 2024
Type: article
Abstract: Recent studies have identified a previously uncharacterized protein C11orf53 (now named POU2AF2/OCA-T1), which functions as a robust co-activator of POU2F3, the master transcription factor which is critical for both normal and neoplastic tuft cell identity and viability. Here, we demonstrate that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements. Loss of POU2AF2 leads to an inhibition of active enhancer nearby genes, such as tuft cell identity genes, and a derepression of Polycomb-dependent poised enhancer nearby genes, which are critical for cell viability and differentiation. Mechanistically, depletion of POU2AF2 results in a global redistribution of the chromatin occupancy of the SWI/SNF complex, leading to a significant 3D genome structure change and a subsequent transcriptional reprogramming. Our genome-wide CRISPR screen further demonstrates that POU2AF2 depletion or SWI/SNF inhibition leads to a PTEN-dependent cell growth defect, highlighting a potential role of POU2AF2-SWI/SNF axis in small cell lung cancer (SCLC) pathogenesis. Additionally, pharmacological inhibition of SWI/SNF phenocopies POU2AF2 depletion in terms of gene expression alteration and cell viability decrease in SCLC-P subtype cells. Therefore, impeding POU2AF2-mediated transcriptional regulation represents a potential therapeutic approach for human SCLC therapy.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, American Cancer Society, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, U.S. Army Medical Research Acquisition Activity
Awards: G1397625732, Computational methods to identify neo-TADs and enhancer-hijacking in rearranged genomes, Visualization, modeling and validation of chromatin interaction data, G2054187885, G2229906039, G3330555382, ROLE OF SUBTYPE-SPECIFIC ESSENTIAL FACTOR NETWORKS IN SMALL CELL LUNG CANCER, G3692266691, G4198559561, G4469160630, G4717980704, G6150573222, Therapeutic targeting deubiquitinase BAP1 in human small cell lung cancer, G9000184192, G9000336729, High throughput interrogation of non-coding variants and 3D genome organization
OpenAlex ID: W4392561152