A04: Vascular lncRNAs in the control of the BRG1 remodelling complex

LncRNAs and chromatin remodeling complexes contribute to epigenetic regulation of gene expression. In the past funding period, we uncovered numerous lncRNA interactions with the SWI/SNF core subunit BRG1. These lncRNAs target or recruit BRG1 to specific genomic sites. For example, lncRNA MANTIS targets endothelial SWI/ SNF to angiogenesis-associated genes and BRG1-interactor LINC00607 facilitates BRG1 binding at ERG-target genes. The molecular mode of the lncRNA-protein interaction is poorly understood. Moreover, we obtained indications that lncRNAs interacting with BRG1 also affect RNA splicing or DNA unwinding. We hypothesize that individual lncRNAs control the targeting of BRG1 to specific regions in the genome to facilitate not only differential gene program execution, but also to regulate the variety of (alternative) transcript isoforms. Moreover, lncRNAs and RNA-interacting proteins could impact on SWI/SNF assembly and its appearance in nuclear condensates. In the upcoming funding period, we will determine the lncRNA-mediated targeting mechanism of BRG1 in different endothelial states, and identify BRG1-binding motifs and domains. The potential regulation of alternative splicing by BRG1-guiding lncRNAs will be studied e.g. on VEGF-receptor FLT1 as well as RNA-dependent complex assembly of SWI/SNF. We will determine the capability of SWI/SNFDNA- lncRNA complexes to affect the 3D chromatin structure by targeting RNA, DNA and protein components of the complex. Subsequent investigation of chromatin interactions will assess the relevance of BRG1 lncRNAcontaining condensates for the cardiovascular system.