Long non-coding RNAs direct the SWI/SNF complex to cell type-specific enhancers
James A. Oo, Timothy Warwick, Katalin Pálfi, Frederike Lam, François 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 Đikić, Michaela Müller-McNicoll, Ralf P. Brandes, Matthias S. Leisegang
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.