Defining transcription factor- chromatin remodeler interactions and their impact on DNA accessibility and gene expression

Abstract

Mammalian SWI/SNF (BAF) complexes are multi-subunit molecular machines that alter nucleosome positioning along DNA to remodel chromatin. The mechanisms by which these complexes achieve cell type-specific genomic recruitment and activities remain relatively uncharacterized. In this study, we identified that the unique DNA motifs for tissue-specific transcription factors (TFs) underlie the site-specific enrichment of BAF complexes across different cell and tissue types. We find that TF expression levels correlate with BAF complex occupancy at corresponding TF motif sites genome-wide and result in transcriptional upregulation of nearest genes. These findings suggest that the collection of expressed TFs plays an important role in establishing cell type-specific BAF complex localization and activity signatures on the genome. To dissect the relationship between TFs and BAF complexes, we overexpressed 14 TFs from a diverse set of TF families in human mesenchymal stem cells (MSCs) and profiled their abilities to re-direct BAF complexes to TF-specific target sites genome-wide. We discovered that expression of lineage-specific TFs results in the recruitment of BAF complexes to de novo target sites, inducing chromatin remodeling and transcriptional activation at nearest genes. Expression of TFs also activate a secondary, downstream network of TFs that further contribute to global patterns of BAF complex recruitment and chromatin accessibility. Further, we determined that select TFs are capable of recruiting the BAF complex core module to de novo sites in the absence of the functional ATPase components of the complex, suggesting that the BAF core module plays a critical role in TF engagement and overall BAF complex recruitment. We used novel biochemical and structural approaches to identify exposed surfaces on the BAF complex core module that interact with TFs. Similarly, using integrative biochemical studies, we identified that TFs interact with BAF complexes through highly conserved regions of their DNA binding domains. Finally, we investigated the role of TF-based BAF-complex recruitment in two examples of TF-perturbed disease states to determine whether this process is a mechanism by which TF-recruitment of BAF complexes enables expression of oncogenic transcriptional programs. Together, these studies provide evidence for TF-based recruitment of BAF chromatin remodeling complexes as a critical mechanism governing cell type-specific accessibility at distal enhancer regions and gene expression in normal development and disease states and provides critical new insight into this biochemical interaction which may be amenable to therapeutic intervention.