Chromatin Occupancy Patterns of GATA and ETS Family Transcription Factors during Megakaryocyte Development

In the course of development of specialized tissues in metazoans, limiting the transcription and translation of genetic material into functional protein is paramount for producing distinct populations of cells with specialized functions. One mechanism by which gene expression is controlled is through lineage-selective sequence-specific DNA binding transcription factors. In the mammalian blood system, the major lineage-selective nuclear factors are members of the GATA and ETS families of transcription factors. GATA1 and GATA2 regulate gene expression in hematopoietic stem cells as well as the progenitors and mature cells of the megakaryocytic and erythroid lineages. Members of the large and diverse ETS family of factors play a role in nearly all of the blood lineages. Here, we used chromatin immunoprecipitation followed by massively parallel sequencing to define and characterize GATA1, GATA2, ETS1, and PU.1 chromatin occupancy in a cell line model of megakaryocyte development. We identify the existence of a prominent and robust "GATA switch" on a genome-wide level in megakaryocytic maturation and our data point to a deterministic role for ETS factors in lineage-specific GATA binding site selection. Moreover, we suggest that PU.1 regulates a previously unappreciated broad transcriptional network in megakaryocytic development. Finally, we discuss our findings in the context of the current state of the field and propose a framework for advancing the understanding of transcriptional regulation of hematopoietic development through the incorporation of novel technologies.