Coactivator condensation drives cell lineage specification

During development, cells make switch-like decisions to activate new gene programs specifying cell lineage. The mechanisms underlying these decisive choices remain unclear. Here we show that the cardiovascular transcriptional coactivator, Myocardin (MYOCD), activates cell identity genes by concentration-dependent and switch-like formation of transcriptional condensates. MYOCD forms such condensates and activates cell identity genes at critical concentration thresholds achieved during smooth muscle cell and cardiomyocyte differentiation. The C-terminal disordered region of MYOCD is necessary and sufficient for condensate formation. Disrupting this region’s ability to form condensates disrupts gene activation. Rescuing condensate formation by replacing this region with disordered regions from functionally unrelated proteins rescues gene activation. Our findings demonstrate that MYOCD condensate formation is required for gene activation during differentiation. We propose that the formation of transcriptional condensates at critical concentrations of cell type-specific regulators provides a molecular switch underlying the activation of key cell identity genes during cell lineage specification. Comparative gene expression profiling analysis of RNA-seq data and MYOCD chromatin occupancy and chromatin accessibility (H3K27ac) by ChIP-seq data for 10T1/2 cells reprogrammed by GFP (control), MYOCD and its different mutants (FUS, deltaTAD, CDT1)