Mechanisms of master regulator hand-off during red blood cell development

So-called master regulators are transcription factor proteins whose individual expression can effect a change in cell identity by either directly co-binding with other factors to target specific gene regulation sites, or through the activation of broad signaling pathways. However, what precipitates the transition from one master-regulated state to another is typically not as well understood. For example, during the developmental transition from hematopoietic stem cells to red blood cells the Gata2 master regulator gives way to Gata1, binding different genomic sites despite their recognition of a similar DNA binding motif. Using ChIP-Seq to identify genome-wide protein binding, the Zon lab at Children’s Hospital has produced a high temporal resolution map of Gata2 and Gata1 binding throughout this transition, along with that of an implicated co-factor, Smad1, and the histone mark H3K27ac. Existing ChIP-Seq analysis techniques predict per-sample transcription factor binding locations, however these methods could miss unique structure only visible in temporal lineage-based data. For this project a unified method would be constructed to identify the specific interplay and ordering of these factors, as well as any dependence on nearby sequence. An understanding of such timing constraints could significantly benefit the in vitro differentiation of hematopoietic stem cells.

Contact: Professor David Gifford, gifford@csail.mit.edu