Fig. 8. Graphical summary.

A Identification of the Shox2-flanking gene desert as a reservoir for distributed transcriptional enhancers with Shox2-overlapping activities in limb, craniofacial, cardiac, and cranial nerve/neuronal cell populations. Light green indicates limb enhancers with highly subregional or limb type restricted activities. B The Shox2 gene desert encodes distributed tissue-specific enhancers that are englobed in a dynamic chromatin domain (D-dom) with tissue-invariant loop anchors and a cardiac-specific high-density contact domain (HCD) that may influence the activity of contained enhancers. Additional gene desert enhancers are likely to participate in the regulation of cardiac Shox2 in SAN progenitors. Dashed line demarcates the VS-250 interval essential for cardiac Shox2 expression⁵⁵. C Cumulative functions of gene desert enhancers orchestrate pleiotropic Shox2 expression essential for proximal limb morphogenesis, craniofacial patterning, and cardiac pacemaker development.