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

Abstract

Developmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. Multiple genome-wide studies have mapped chromatin and genomic features of such elements. However, the enhancer definition is operational, and no global experiments have been conducted to date that identify their cell type and cell stage-specific transcription stimulatory activity in a chromatin context. Here, we describe a high-throughput method that identifies thousands of cis-elements capable of stimulating transcriptional activity from a minimal promoter using the blood progenitor differentiation from embryonic stem cells as model. We show that hematopoietic specification and blood cell-specific gene expression are 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 presents a major advance in our understanding of developmental gene expression control in the hematopoietic system and beyond.

Genome-wide transcription factor–binding maps reveal cell-specific changes in the regulatory architecture of human HSPCs

“…However, identifying enhancers with appropriate spatiotemporal activity is not trivial. While experimental techniques for massively parallel interrogation of enhancer activity and specificity have been developed 74,63 , our data provides a catalogue of putative enhancers that could fast track functional studies.…”