Abstract The coordination of chromatin remodeling is essential for DNA accessibility and gene expression control 1 . 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 2 . Despite the absence of a defined DNA recognition motif, SWI/SNF binds lineage specific enhancers genome-wide where it actively maintains open chromatin state 2–5 . It does so while retaining the ability to respond dynamically to cellular signals 4 . 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 a competitive recruitment of SWI/SNF by lncRNAs which provide a specific and dynamic layer of control in chromatin accessibility and gene expression.

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