Gene regulatory logic reflects the occupancy of cis elements by transcription factors and the configuration of promoters and enhancers. As the majority of genome-wide analyses have focused on adult cells, scant attention has been paid to embryonic cells, other than embryonic stem cells. Focusing on genome-wide comparative analyses of two stages of erythroblasts, we discovered that regulation of embryonic-specific genes is promoter-centric through Gata1, whereas adult-specific control is combinatorial enhancer-driven and requires Myb, which is confirmed by increased enhancer–promoter interactions of adult specific genes. Extending genome-wide comparative analyses more broadly to available datasets of diverse mouse and human cells and tissues, we conclude that the progressively increased enhancer dependence of cell-type–specific genes with developmental age is conserved during development.
