Early enhancer establishment and regulatory locus complexity shape transcriptional programs in hematopoietic differentiation

We carried out an integrative analysis of enhancer landscape and gene expression dynamics in hematopoietic differentiation using DNase-seq, histone mark ChIP-seq, and RNA-seq to model how early establishment of enhancers and regulatory locus complexity govern gene expression changes at cell state transitions. We found that high complexity genes – i.e. those with large total number of DNase-mapped enhancers across the lineage – differ architecturally and functionally from low complexity genes, achieve larger expression changes, and are enriched for both cell-type specific and “transition” enhancers, which are established in hematopoietic stem and progenitor cells and maintained in one differentiated cell fate but lost in others. We then developed a quantitative model to accurately predict gene expression changes from the DNA sequence content and lineage history of active enhancers. Our method suggests a novel mechanistic role for PU.1 at transition peaks in B cell specification and can be used to correct enhancer-gene assignments.