BMP signaling cooperates with GATA factors to govern stage-specific gene expression during erythroid differentiation [ATAC-Seq]

Hematopoietic progenitors respond to developmental and environmental cues to differentiate. The stage-specific steps of differentiation are stereotypic for each cell lineage, and are controlled by transcription. Here we investigate how differential genomic binding of signal-responsive and lineage-restricted transcription factors can specify subsequent stages of erythropoiesis. Using a human erythroid differentiation system, we extensively characterized the co-operation of the BMP signaling transcription factor SMAD1 with the erythroid transcription factors GATA2 and GATA1 in a detailed time-course. BMP signaling enhances erythroid differentiation. SMAD1 is co-recruited with GATA factors at stage-specific genes that are required to have high expression in each stage. Additionally, we observed SMAD1-GATA co-enriched regions are within super-enhancers and span accessible chromatin. Co-bound regions harbor cell-type specific transcription factor motifs that change during commitment, in contrast to GATA-alone regions. Our studies demonstrate that signal-responsive factors together with lineage regulators mark genomic “hotspots” that function to regulate stage-specific gene expression. ATAC-seq was performed, after a 2hr pulse of hrBMP, on progenitor and differentiating cells at 6 hours and daily from days 1 through 5 days of erythroid differentiation.