All avired up: heptads in hematopoiesis

In this edition of Blood, Subramanian et al provide important new insights into the complex transcriptional regulatory networks governing human hematopoietic differentiation.(1) Following recent work from this group that identified a triad of transcription factors (TFs) (GATA2-TAL1-ERG) that formed regulatory circuits controlling erythroid transition in bulk CD34(+) cells,(2) this study defined a "connectivity map" of selective TF binding sites for a predefined "heptad" factors (FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2)(3) as well as other chromatin marks in several populations of human hematopoietic stem and progenitor cells. This vast resource was analyzed for patterns of binding and chromatin interactions across these populations, providing insights into the dynamic remodeling of proposed regulatory circuits controlled by heptad TFs during early human hematopoiesis. Importantly, this analysis led to novel regulatory elements linked to key hematopoietic genes being proposed, including heptad genes themselves, with motif analysis of active noncoding cis-regulatory elements (CREs) demonstrating a "grammar" underlying cell type-specific putative enhancer activity, with a random forest-based machine learning approach able to link regulatory motifs to cell identity (see figure).