High-Resolution Epigenomic Atlas of Human Embryonic Craniofacial Development

Abstract

Summary: Defects in patterning during human embryonic development frequently result in craniofacial abnormalities. The gene regulatory programs that build the craniofacial complex are likely controlled by information located between genes and within intronic sequences. However, systematic identification of regulatory sequences important for forming the human face has not been performed. Here, we describe comprehensive epigenomic annotations from human embryonic craniofacial tissues and systematic comparisons with multiple tissues and cell types. We identified thousands of tissue-specific craniofacial regulatory sequences and likely causal regions for rare craniofacial abnormalities. We demonstrate significant enrichment of common variants associated with orofacial clefting in enhancers active early in embryonic development, while those associated with normal facial variation are enriched near the end of the embryonic period. These data are provided in easily accessible formats for both craniofacial researchers and clinicians to aid future experimental design and interpretation of noncoding variation in those affected by craniofacial abnormalities. : Wilderman et al. report the global identification of gene regulatory sequences active in early human craniofacial development. Systematic comparisons with over 120 different human tissues and cell types reveal shared and craniofacial-specific enhancers. Craniofacial enhancers are enriched with genetic associations for both orofacial clefting risk and face shape. Keywords: development, genomics, epigenomics, craniofacial, chromatin state, orofacial clefting, cleft palate, cleft lip, developmental enhancer, cis-regulatory sequence, transcriptional enhancer