Long non-coding RNAs direct the SWI/SNF complex to cell type-specific enhancers

  • Nat Commun. 2025 Jan 2;16(1):131. doi: 10.1038/s41467-024-55539-6.
James A Oo  1  2  3 ,  Timothy Warwick  1  2  3 ,  Katalin Pálfi  1 ,  Frederike Lam  1  2  3 ,  Francois McNicoll  4 ,  Cristian Prieto-Garcia  5  6 ,  Stefan Günther  7 ,  Can Cao  1  8  9 ,  Yinuo Zhou  1  2  3 ,  Alexey A Gavrilov  10 ,  Sergey V Razin  10  11 ,  Alfredo Cabrera-Orefice  1  12 ,  Ilka Wittig  1  12 ,  Soni Savai Pullamsetti  13  14 ,  Leo Kurian  1  2  3 ,  Ralf Gilsbach  1  8  9 ,  Marcel H Schulz  2  3  15 ,  Ivan Dikic  3  5  6 ,  Michaela Müller-McNicoll  3  4  16 ,  Ralf P Brandes  1  2  3 ,  Matthias S Leisegang  17  18  19
Affiliations
  • 1. Goethe University Frankfurt, Institute for Cardiovascular Physiology, Frankfurt, Germany.
  • 2. German Center of Cardiovascular Research (DZHK), Partner site Rhein/Main, Frankfurt, Germany.
  • 3. Cardio-Pulmonary Institute (CPI), Goethe University Frankfurt, Frankfurt, Germany.
  • 4. Goethe University Frankfurt, Institute for Molecular Biosciences, Frankfurt, Germany.
  • 5. Goethe University Frankfurt, Institute of Biochemistry II, Faculty of Medicine, Frankfurt, Germany.
  • 6. Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Frankfurt, Germany.
  • 7. Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 8. Institute of Experimental Cardiology, Heidelberg University Hospital, Heidelberg, Germany.
  • 9. German Center of Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim, Heidelberg, Germany.
  • 10. Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
  • 11. Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
  • 12. Goethe University Frankfurt, Functional Proteomics Center, Frankfurt, Germany.
  • 13. Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
  • 14. Cardio-Pulmonary Institute (CPI), University of Giessen, Giessen, Germany.
  • 15. Goethe University Frankfurt, Institute for Computational Genomic Medicine, Frankfurt, Germany.
  • 16. Max Planck Institute for Biophysics, Frankfurt, Germany.
  • 17. Goethe University Frankfurt, Institute for Cardiovascular Physiology, Frankfurt, Germany. [email protected].
  • 18. German Center of Cardiovascular Research (DZHK), Partner site Rhein/Main, Frankfurt, Germany. [email protected].
  • 19. Cardio-Pulmonary Institute (CPI), Goethe University Frankfurt, Frankfurt, Germany. [email protected].
PMID: 39747144 DOI: 10.1038/s41467-024-55539-6
Abstract

The coordination of chromatin remodeling is essential for DNA accessibility and gene expression control. The highly conserved and ubiquitously expressed SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex plays a central role in cell type- and context-dependent gene expression. Despite the absence of a defined DNA recognition motif, SWI/SNF binds lineage specific enhancers genome-wide where it actively maintains open chromatin state. It does so while retaining the ability to respond dynamically to cellular signals. However, the mechanisms that guide SWI/SNF to specific genomic targets have remained elusive. Here we demonstrate that trans-acting long non-coding RNAs (lncRNAs) direct the SWI/SNF complex to cell type-specific enhancers. SWI/SNF preferentially binds lncRNAs and these predominantly bind DNA targets in trans. Together they localize to enhancers, many of which are cell type-specific. Knockdown of SWI/SNF- and enhancer-bound lncRNAs causes the genome-wide redistribution of SWI/SNF away from enhancers and a concomitant differential expression of spatially connected target genes. These lncRNA-SWI/SNF-enhancer networks support an enhancer hub model of SWI/SNF genomic targeting. Our findings reveal that lncRNAs competitively recruit SWI/SNF, providing a specific and dynamic layer of control over chromatin accessibility, and reinforcing their role in mediating enhancer activity and gene expression.

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