title: Early enhancer establishment and regulatory locus complexity shape transcriptional programs in hematopoietic differentiation.
abstract: 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.
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Alvaro J
authors.initials: AJ
authors.lastname: González
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Manu
authors.initials: M
authors.lastname: Setty
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Leslie
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012044:Regression Analysis; D013997:Time Factors
chemical_list: D006657:Histones; D008239:Lysine