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

Nat Genet. 2015 Nov;47(11):1249-59. doi: 10.1038/ng.3402. Epub 2015 Sep 21.


We carried out an integrative analysis of enhancer landscape and gene expression dynamics during hematopoietic differentiation using DNase-seq, histone mark ChIP-seq and RNA sequencing to model how the early establishment of enhancers and regulatory locus complexity govern gene expression changes at cell state transitions. We found that high-complexity genes-those with a 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 new mechanistic role for PU.1 at transition peaks during B cell specification and can be used to correct assignments of enhancers to genes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cell Lineage / genetics
  • Enhancer Elements, Genetic / genetics*
  • Gene Expression Regulation*
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Methylation
  • Models, Genetic
  • Promoter Regions, Genetic / genetics*
  • Regression Analysis
  • Time Factors


  • Histones
  • Lysine