2. Academic Validation
  3. A SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer

A SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer

  • Nat Commun. 2024 Mar 7;15(1):2067. doi: 10.1038/s41467-024-46492-5.
Aileen Szczepanski # 1 2,  Natsumi Tsuboyama # 1 2,  Huijue Lyu # 1 2,  Ping Wang 1 2,  Oguzhan Beytullahoglu 1 2,  Te Zhang 1 2,  Benjamin David Singer 1 2 3,  Feng Yue 1 2 4,  Zibo Zhao 5 6,  Lu Wang 7 8
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • 2 Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • 3 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • 4 Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 5 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. [email protected].
  • 6 Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. [email protected].
  • 7 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. [email protected].
  • 8 Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. [email protected].
  • # Contributed equally.
PMID: 38453939 DOI: 10.1038/s41467-024-46492-5
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.

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