GRHL2 and AP2a coordinate early surface ectoderm lineage commitment during development
Ann E. Collier,
Samantha N. Piekos,
Angela Liu,
Jillian M. Pattison,
Franco Felix,
Alessandro A. Bailetti,
Egor Sedov,
Sadhana Gaddam,
Hanson Zhen,
Anthony E. Oro
Affiliations
Ann E. Collier
Program in Epithelial Biology, Stanford University, Stanford, CA USA
Samantha N. Piekos
Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University, Stanford, CA USA
Angela Liu
Program in Epithelial Biology, Stanford University, Stanford, CA USA; Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University, Stanford, CA USA
Jillian M. Pattison
Program in Epithelial Biology, Stanford University, Stanford, CA USA
Franco Felix
Program in Epithelial Biology, Stanford University, Stanford, CA USA; Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University, Stanford, CA USA
Alessandro A. Bailetti
Program in Epithelial Biology, Stanford University, Stanford, CA USA
Egor Sedov
Program in Epithelial Biology, Stanford University, Stanford, CA USA
Sadhana Gaddam
Program in Epithelial Biology, Stanford University, Stanford, CA USA
Hanson Zhen
Program in Epithelial Biology, Stanford University, Stanford, CA USA
Anthony E. Oro
Program in Epithelial Biology, Stanford University, Stanford, CA USA; Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University, Stanford, CA USA; Corresponding author
Summary: Ectodermal dysplasias including skin abnormalities and cleft lip/palate result from improper surface ectoderm (SE) patterning. However, the connection between SE gene regulatory networks and disease remains poorly understood. Here, we dissect human SE differentiation with multiomics and establish GRHL2 as a key mediator of early SE commitment, which acts by skewing cell fate away from the neural lineage. GRHL2 and master SE regulator AP2a balance early cell fate output, with GRHL2 facilitating AP2a binding to SE loci. In turn, AP2a restricts GRHL2 DNA binding away from de novo chromatin contacts. Integration of these regulatory sites with ectodermal dysplasia-associated genomic variants annotated within the Biomedical Data Commons identifies 55 loci previously implicated in craniofacial disorders. These include ABCA4/ARHGAP29 and NOG regulatory regions where disease-linked variants directly affect GRHL2/AP2a binding and gene transcription. These studies elucidate the logic underlying SE commitment and deepen our understanding of human oligogenic disease pathogenesis.
