Combinatorial Assembly of Developmental Stage-Specific Enhancers Controls Gene Expression Programs during Human Erythropoiesis

Jian Xu, Zhen Shao, Kimberly Glass, Daniel E. Bauer, Luca Pinello, Ben Van Handel, Serena Hou, John A. Stamatoyannopoulos, Hanna K A Mikkola, Guo Cheng Yuan, Stuart H. Orkin

Research output: Contribution to journalArticle

110 Scopus citations

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. Xu et al. investigate human fetal and adult erythroid gene expression programs by comparative transcriptome, transcription factor, and chromatin profiling. They demonstrate that lineage-specifying master regulators and chromatin modifications at regulatory enhancers are relatively static platforms; fetal/adult-stage specificity of gene expression is controlled by a distinct layer of transcriptional coregulators.

Original languageEnglish (US)
Pages (from-to)796-811
Number of pages16
JournalDevelopmental cell
Volume23
Issue number4
DOIs
StatePublished - Oct 16 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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    Xu, J., Shao, Z., Glass, K., Bauer, D. E., Pinello, L., Van Handel, B., Hou, S., Stamatoyannopoulos, J. A., Mikkola, H. K. A., Yuan, G. C., & Orkin, S. H. (2012). Combinatorial Assembly of Developmental Stage-Specific Enhancers Controls Gene Expression Programs during Human Erythropoiesis. Developmental cell, 23(4), 796-811. https://doi.org/10.1016/j.devcel.2012.09.003