Sc-Multiome Reveals a Time-dependent Regulatory Role of MECOM in Vascular Development

Abstract

Vascular development requires the precise coordination of endothelial and mural cell differentiation through tightly regulated intercellular signaling. MECOM is an established endothelial identity gene associated with endothelial lineage specification, yet its broader regulatory role during vascular development remains unclear. Using integrative single-cell transcriptomic and chromatin accessibility analyses across human vascular organoid and mouse embryonic heart, this study demonstrates that MECOM loss disrupts both endothelial and mural cell fate specification, resulting in dysregulation of vascular lineage composition during vascular development. Moreover, MECOM ablation promotes the activity of key intercellular signaling pathways for vascular development at early development stage, whereas such pathways exhibit reduced signaling activity upon MECOM knockout (KO). Specifically, TGF-β signaling is identified as a key pathway subject to this MECOM-mediated temporal regulation in both human organoid and mouse heart. Single-cell chromatin accessibility analysis further revealed that Mecom-KO increases accessibility at TGF-β pathway gene loci, suggesting its role in epigenetic regulation over key vascular signaling pathways. These findings establish MECOM as a temporal gatekeeper of vascular intercellular signaling, coordinating the differentiation of both endothelial and mural lineages through precise regulation of developmental pathway activity and chromatin accessibility during vascular development.