LncRNA adapters determine SWI/SNF complex occupancy at gene regulatory elements [CutAndRun_PROTAC]

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 key role in regulating gene expression in a context-dependent manner. SWI/SNF actively maintains open chromatin states across the genome and responds dynamically to cellular signals. However, the precise mechanisms determining how SWI/SNF is targeted to specific genomic sites remain elusive. In this study we demonstrate that long non-coding RNAs (lncRNAs) are pivotal in the binding of the SWI/SNF complex to specific genomic targets. The interaction between SWI/SNF and lncRNAs is essential for the recruitment of the complex to gene regulatory elements, where it plays a critical role. We show that trans-acting lncRNAs direct the SWI/SNF complex to cell-specific enhancers, with lncRNA knockdowns leading to a genome-wide redistribution of SWI/SNF away from these enhancers. This redistribution impacts the expression of genes connected to these enhancers, underscoring the critical role of lncRNAs in the specific targeting of SWI/SNF to DNA. This insight into the targeting mechanisms of SWI/SNF by lncRNAs has broad implications, from understanding the processes of gene expression control to identifying therapeutic targets in diseases associated with SWI/SNF dysfunction, such as cancer. To investigate which gene regulatory elements depend on BRG1 for their chromatin accessibility, CUT&RUN-sequencing was performed in HUVEC treated with a PROTAC against BRG1 at different time points.