ROLE OF CHROMATIN REMODELING BAF COMPLEX IN CARDIOVASCULAR DEVELOPMENT AND DISEASE

Abstract

The BAF complex plays a vital role in the development of a wide range of tissues by modulating gene expression programs at the chromatin level. However, the role of the BAF complex in cardiovascular system development has remained unclear. To determine it, we deleted BAF155/BAF170, the core subunits required for the assembly and functions of the BAF complex in neural crest cells (NCCs) and cardiomyocytes. Neural crest-specific deletion of BAF155/170 leads to embryonic lethality due to cardiovascular defects. Transcriptomic analysis revealed that the BAF complex modulates the gene expression of signaling pathways, including Hippo and Notch, essential for the migration, proliferation, and differentiation of the NCCs. BAF complex is also crucial for the Brg1-Yap-Tead-dependent transcription of target genes in NCCs. On the other hand, cardiomyocyte-specific deletion of either BAF155 or BAF170 leads to dilated cardiomyopathy and heart failure in adult mice. Transcriptomic and molecular analyses showed that the BAF complex modulates the MAPK signaling pathway, in part by regulating Uts2b expression in the developing heart. Together, our results demonstrate an essential role of the BAF complex in cardiovascular development and function.