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

James A. Oo, Timothy Warwick, Katalin Pálfi, Frederike Lam, Francois McNicoll, Cristian Prieto-Garcia, Stefan Günther, Can Cao, Yinuo Zhou, Alexey A. Gavrilov, Sergey V. Razin, Alfredo Cabrera-Orefice, Ilka Wittig, Soni Savai Pullamsetti, Leo Kurian, Ralf Gilsbach, Marcel H. Schulz, Ivan Dikic, Michaela Müller-McNicoll, Ralf P. Brandes and Matthias S. Leisegang ()
Additional contact information
James A. Oo: Institute for Cardiovascular Physiology
Timothy Warwick: Institute for Cardiovascular Physiology
Katalin Pálfi: Institute for Cardiovascular Physiology
Frederike Lam: Institute for Cardiovascular Physiology
Francois McNicoll: Institute for Molecular Biosciences
Cristian Prieto-Garcia: Faculty of Medicine
Stefan Günther: Max Planck Institute for Heart and Lung Research
Can Cao: Institute for Cardiovascular Physiology
Yinuo Zhou: Institute for Cardiovascular Physiology
Alexey A. Gavrilov: Russian Academy of Sciences
Sergey V. Razin: Russian Academy of Sciences
Alfredo Cabrera-Orefice: Institute for Cardiovascular Physiology
Ilka Wittig: Institute for Cardiovascular Physiology
Soni Savai Pullamsetti: Justus Liebig University
Leo Kurian: Institute for Cardiovascular Physiology
Ralf Gilsbach: Institute for Cardiovascular Physiology
Marcel H. Schulz: Partner site Rhein/Main
Ivan Dikic: Goethe University Frankfurt
Michaela Müller-McNicoll: Goethe University Frankfurt
Ralf P. Brandes: Institute for Cardiovascular Physiology
Matthias S. Leisegang: Institute for Cardiovascular Physiology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55539-6

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