title: Combinatorial assembly of developmental stage-specific enhancers controls gene expression programs during human erythropoiesis.
abstract: Gene-distal enhancers are critical for tissue-specific gene expression, but their genomic determinants within a specific lineage at different stages of development are unknown. Here we profile chromatin state maps, transcription factor occupancy, and gene expression profiles during human erythroid development at fetal and adult stages. Comparative analyses of human erythropoiesis identify developmental stage-specific enhancers as primary determinants of stage-specific gene expression programs. We find that erythroid master regulators GATA1 and TAL1 act cooperatively within active enhancers but confer little predictive value for stage specificity. Instead, a set of stage-specific coregulators collaborates with master regulators and contributes to differential gene expression. We further identify and validate IRF2, IRF6, and MYB as effectors of an adult-stage expression program. Thus, the combinatorial assembly of lineage-specific master regulators and transcriptional coregulators within developmental stage-specific enhancers determines gene expression programs and temporal regulation of transcriptional networks in a mammalian genome.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shao
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Bauer
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.forename: Ben
authors.initials: B
authors.lastname: Van Handel
authors.forename: Serena
authors.initials: S
authors.lastname: Hou
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.forename: Hanna K A
authors.initials: HK
authors.lastname: Mikkola
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D004920:Erythropoiesis / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D050982:GATA1 Transcription Factor; D050836:Interferon Regulatory Factor-2; D050835:Interferon Regulatory Factors; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C494688:GATA1 protein, human; C494229:IRF2 protein, human; C109803:IRF6 protein, human; C067143:TAL1 protein, human