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

Oo, J. A.; Warwick, T.; Palfi, K.; McNicoll, F.; Cao, C.; Prieto-Garcia, C.; Zhou, Y.; Gavrilov, A. A.; Razin, S. V.; Lam, F.; Günther, S.; Cabrera-Orefice, A.; Wittig, I.; Pullamsetti, S. S.; Kurian, L.; Gilsbach, R.; Schulz, M.; Dikic, I.; Müller-McNicoll, M.; Brandes, R. P.; Leisegang, M. S.

doi:10.1101/2024.03.21.585172

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bioRxiv · 10.1101/2024.03.21.585172

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

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Abstract

The coordination of chromatin remodeling is essential for DNA accessibility and gene expression control1. 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 expression2. Despite the absence of a defined DNA recognition motif, SWI/SNF binds lineage specific enhancers genome-wide where it actively maintains open chromatin state2-5. It does so while retaining the ability to respond dynamically to cellular signals4. 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.

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Oo, J. A., Warwick, T., Palfi, K., McNicoll, F., Cao, C., Prieto-Garcia, C., Zhou, Y., Gavrilov, A. A., Razin, S. V., Lam, F., Günther, S., Cabrera-Orefice, A., Wittig, I., Pullamsetti, S. S., Kurian, L., Gilsbach, R., Schulz, M., Dikic, I., Müller-McNicoll, M., Brandes, R. P., Leisegang, M. S.. 2024-03-21. Long non-coding RNAs direct the SWI/SNF complex to cell-specific enhancers. https://doi.org/10.1101/2024.03.21.585172

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