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Enhancer-Dependence of Cell-Type-Specific Gene Expression Increases with Developmental Age

Abstract Text

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

Wenqing Cai1,7, Jialiang Huang1,2,5,7, Qian Zhu1,2, Bin E. Li1, Davide Seruggia1, Pingzhu Zhou3, Minh Nguyen1, Yuko Fujiwara1, Huafeng Xie1, Zhenggang Yang5, Danni Hong5, Pengfei Ren5, Jian Xu4, William T. Pu3, Guo-Cheng Yuan2,* and Stuart H. Orkin1,6,8,*

1Cancer and Blood Disorders Center, Boston Children’s Hospital and Dana-Farber Cancer Institute, Harvard Medical School; 2Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard T.H.Chan School of Public Health; 3Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02215, USA; 4Children’s Medical Center Research Institute, Department of Pediatrics, University of Texas at Southwestern Medical Center, Dallas, TX, USA; 5State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; 6Howard Hughes Medical Institute, Boston, MA 02115, USA; 7These authors contributed equally; *Corresponding author

How overall principles of cell-type-specific gene regulation (the "logic") may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic and 3D-genomic profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in the active histone mark, H3K27ac, and the occupancy of lineage-specific transcription factors, Gata1 and Myb. The activation of EryD-specific distal enhancers and the EryD-specific distal occupancy of Gata1 require Myb. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes employ distal enhancers for long-range regulation through enhancer-promoter looping, confirmed by Gata1 HiChIP. CRISPR/Cas9 mediated genome editing in selected loci demonstrated 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 enhancers with increasing age of ontogeny among diverse primary cells and tissues of mouse and human origin. Our findings highlight fundamental and conserved differences in regulatory logic at distinct developmental stages, characterized by simpler promoter-centric regulation in embryonic cells and combinatorial enhancer-driven control in adult cells.