Aberrations in tissue-specific enhancers underlie many developmental defects. Disrupting a noncoding region distal from the human SOX9 gene causes the Pierre Robin sequence (PRS) characterized by the undersized lower jaw. Such a craniofacial-specific defect has been previously linked to enhancers transiently active in cranial neural crest cells (CNCCs). We demonstrate that the PRS region also strongly regulates Sox9 in CNCC-derived Meckel's cartilage (MC), but not in limb cartilages, even after decommissioning of CNCC enhancers. Such an MC-specific regulatory effect correlates with the MC-specific chromatin contacts between the PRS region and Sox9, highlighting the importance of lineage-dependent chromatin topology in instructing enhancer usage. By integrating the enhancer signatures and chromatin topology, we uncovered >10,000 enhancers that function differentially between MC and limb cartilages and demonstrated their association with human diseases. Our findings provide critical insights for understanding the choreography of gene regulation during development and interpreting the genetic basis of craniofacial pathologies.