Enhancer dependence of cell-type–specific gene expression increases with developmental age

Wenqing Cai, Jialiang Huang, Qian Zhu, Bin E. Li, Davide Seruggia, Pingzhu Zhou, Minh Nguyen, Yuko Fujiwara, Huafeng Xie, Zhenggang Yang, Danni Hong, Pengfei Ren, Jian Xu, William T. Pu, Guo Cheng Yuan, Stuart H. Orkin

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


How overall principles of cell-type–specific gene regulation (the “logic”) may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic, and three-dimensional (3D) genomic profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1, and Myb occupancy. EryP-/EryD-shared enhancers are highly correlated with red blood cell identity genes, whereas cell-type–specific regulation employs different cis elements in EryP and EryD cells. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes rely more on distal enhancers for regulation involving Myb-mediated enhancer activation. Gata1 HiChIP demonstrated an overall increased enhancer–promoter interactions at EryD-specific genes, whereas genome editing in selected loci confirmed distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer dependence of transcription, we observed a progressive reliance on cell-specific enhancers with increasing ontogenetic age among diverse tissues of mouse and human origin. Our findings highlight fundamental and conserved differences at distinct developmental stages, characterized by simpler promoter-centric regulation of cell-type–specific genes in embryonic cells and increased combinatorial enhancer-driven control in adult cells.

Original languageEnglish (US)
Pages (from-to)21450-21458
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
StatePublished - Sep 1 2020


  • Enhancer
  • Erythropoiesis
  • GATA1
  • HiChIP
  • Myb

ASJC Scopus subject areas

  • General


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