A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification

Defining cis-regulatory elements is an important goal in understanding how gene expression is regulated. Here the authors show blood cell-specific gene expression is controlled by the action of thousands of differentiation stage-specific sets of cis-elements that respond to cytokine signals terminating at signaling responsive transcription factors. Developmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. To date no global experiments have been conducted that identify their cell type and cell stage-specific activity within one developmental pathway and in a chromatin context. Here, we describe a high-throughput method that identifies thousands of differentially active cis-elements able to stimulate a minimal promoter at five stages of hematopoietic progenitor development from embryonic stem (ES) cells, which can be adapted to any ES cell derived cell type. We show that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of cis-elements which respond to cytokine signals terminating at signalling responsive transcription factors. Our work provides an important resource for studies of hematopoietic specification and highlights the mechanisms of how and where extrinsic signals program a cell type-specific chromatin landscape driving hematopoietic differentiation.

Automated summary

The study reveals that blood cell-specific gene expression is regulated by thousands of differentiation stage-specific cis-elements that respond to cytokine signals terminating at signaling responsive transcription factors. This is an important finding for understanding the mechanisms of hematopoietic differentiation. The authors also describe a high-throughput method to identify differentially active cis-elements in hematopoietic progenitor development, which can be applied to other cell types derived from embryonic stem cells.