GSE112717
Enhancer-dependence of gene expression increases with developmental age
How overall principles of gene regulation (the "logic") may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic and topological 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. 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. Genome editing 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 enhancer control 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. Overall design: In order to profile chromatin structure and organization during the ontogeny of primitive and definitive erythroblasts, we used two cell surface-markers CD71 and Ter119, which were used in previous studies to define and distinguish erythroblasts, to FACS isolate CD71+/Ter119+ primitive (EryP) and definitive erythroblasts (EryD) from E10.5 embryonic peripheral blood and E13.5 fetal liver, respectively. FACS sorted cells were subsequently used for profiling of chromatin accessibility, histone modifications, master TFs occupancy and chromatin interactions profiles. The genome-wide transcriptome profilings were determined by RNA-seq, and were used throughout the whole study as reference to evaluate the association between chromatin features and transcription.