The study investigates the role of DNA-guided cooperativity in shaping face and limb mesenchyme during embryonic development. The 'Coordinator' motif, a composite of common motifs bound by basic helix-loop-helix (bHLH) and homeodomain (HD) transcription factors (TFs), is identified as a key regulator in these processes. TWIST1, a bHLH TF, and a collective of HD factors, including ALX1, ALX4, MSX1, and PRRX1, are shown to cooperatively bind at Coordinator sites, guiding the integration of cellular and positional identity programs. TWIST1 is essential for HD binding and open chromatin at Coordinator sites, while HD factors stabilize TWIST1 occupancy and titrate it away from non-Coordinator sites. This cooperativity results in shared regulation of genes involved in cell-type and positional identities, ultimately shaping facial morphology and evolution. The study also explores the biochemical and structural mechanisms underlying this cooperativity, demonstrating how the TWIST1 loop and DNA sequence guide the interaction between TWIST1 and HD TFs. Finally, the study links the roles of Coordinator-binding TFs and their genomic targets to human phenotypic variation, suggesting that genetic variants affecting Coordinator-containing regulatory regions modulate facial shape.The study investigates the role of DNA-guided cooperativity in shaping face and limb mesenchyme during embryonic development. The 'Coordinator' motif, a composite of common motifs bound by basic helix-loop-helix (bHLH) and homeodomain (HD) transcription factors (TFs), is identified as a key regulator in these processes. TWIST1, a bHLH TF, and a collective of HD factors, including ALX1, ALX4, MSX1, and PRRX1, are shown to cooperatively bind at Coordinator sites, guiding the integration of cellular and positional identity programs. TWIST1 is essential for HD binding and open chromatin at Coordinator sites, while HD factors stabilize TWIST1 occupancy and titrate it away from non-Coordinator sites. This cooperativity results in shared regulation of genes involved in cell-type and positional identities, ultimately shaping facial morphology and evolution. The study also explores the biochemical and structural mechanisms underlying this cooperativity, demonstrating how the TWIST1 loop and DNA sequence guide the interaction between TWIST1 and HD TFs. Finally, the study links the roles of Coordinator-binding TFs and their genomic targets to human phenotypic variation, suggesting that genetic variants affecting Coordinator-containing regulatory regions modulate facial shape.