Meta-analysis of epigenetic remodeling reveals CRX’s mechanism of action in retinal development

Transcription factors (TFs) acting during development often direct chromatin remodeling to allow for and promote gene expression. However, our knowledge of TFs is largely limited to their regulatory activity in plasmid-based reporter assays. To overcome this limitation, we investigated the importance of the photoreceptor TF CRX in remodeling the rod epigenome over development. By performing ATAC-seq in WT and Crx-deficient retinas, and analyzing the data alongside other genome-wide datasets, we determined that CRX is only required for remodeling or sustaining activity of <1/3 of its binding sites. These CRX-Dependent sites are defined by developmental epigenetic remodeling and the expression of nearby genes that rely on CRX. Collectively, CRX acts as a master TF to execute rod differentiation by exerting distinct and overlapping functions in chromatin rearrangement. Our study serves as a model for investigating other cell type-specific TFs and highlights the importance of analyzing TF activities at multiple levels.