Consistent with previous findings, we identified cases where gene expression changes ‘lagged’ behind variation in chromatin accessibility. For example, while myeloperoxidase (MPO) expression is expressed in granulocyte-macrophage progenitors (GMP) and is associated with myeloid fate commitment47,48, the regulatory region immediately upstream acquired accessibility in lymphoid-primed multipotent progenitors (LMPP) (Fig. 2h-j). We utilized a cross-correlation-based metric to systematically identify 236 ‘lagging’ loci (Supplementary Methods) across this trajectory. KEGG pathway enrichment analysis revealed a strong enrichment for genes involved in cell cycle and DNA replication (Fig. 2k). These loci were characterized by accessible chromatin at the earliest stages of differentiation (hematopoietic stem cells), but there is a delay before the associated genes become transcriptionally active (Fig. 2l). The accessible state of these loci in the earliest progenitors may represent a form of priming to enable rapid cell-cycle entry once the decision to differentiate has been made and represents the type of discovery that can be enabled through integrative analysis across modalities.
