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

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

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. Leisegang@vrc.uni-frankfurt.de.
  • 18 German Center of Cardiovascular Research (DZHK), Partner site Rhein/Main, Frankfurt, Germany. Leisegang@vrc.uni-frankfurt.de.
  • 19 Cardio-Pulmonary Institute (CPI), Goethe University Frankfurt, Frankfurt, Germany. Leisegang@vrc.uni-frankfurt.de.
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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