SUMMARYDefects 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.

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.

12 13 Defects in embryonic patterning resulting in craniofacial abnormalities are common birth 14 defects affecting up to 1 in 500 live births worldwide, and are mostly non-syndromic. 15 The regulatory programs that build and shape the craniofacial complex are thought to 16 be controlled by information encoded in the genome between genes and within intronic 17 sequences. Early stages of human craniofacial development have not been interrogated 18 with modern functional genomics techniques, preventing systematic analysis of genetic 19 associations with craniofacial-specific regulatory sequences. Here we describe a 20 comprehensive resource of craniofacial epigenomic annotations and systematic, 21 integrative analysis with a variety of human tissues and cell types. We identified 22 thousands of novel craniofacial enhancers and provide easily accessible genome 23 annotations for craniofacial researchers and clinicians. We demonstrate the utility of our 24 data to find likely causal variants for craniofacial abnormalities and identify a large 25 enhancer cluster that interacts with HOXA genes during craniofacial development.