Genome-Wide Programming of Myeloid Cell Fates

Abstract SCI-29

Hematopoiesis represents one of the most tractable models of adult stem cell development and differentiation. Transcription factor (TF) proteins have long been recognized as major regulators of blood stem cell development as well as the subsequent differentiation into the multiple mature hematopoietic lineages. Seminal studies in multiple vertebrate model systems have identified specific TFs that control cell fate choices during myeloid differentiation (1). It remains largely unknown, however, how individual TFs are integrated into wider transcriptional regulatory networks, and how combinatorial TF interactions within these networks drive lineage specific gene expression programs. We are addressing these issues using two complementary approaches. First, we use a combination of transgenic reporter assays and network modeling approaches to reconstruct core transcription factor networks operating in early myeloid differentiation. Second, we employ genome-scale analysis of transcription factor binding sites for key hematopoietic regulators in both stem/progenitor cells and mature lineages (2,3). Integrated analysis of genome-scale datasets reveals previously unrecognized combinatorial interactions within core hematopoietic regulatory networks, which can be validated using both biochemical and mouse knockout approaches. Moreover, our studies also pinpoint novel candidate hematopoietic regulators, several of which we have validated using high throughput loss-of-function assays in zebrafish.