High Resolution Epigenomic Atlas of Early Human Craniofacial Development

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 have 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 non-coding variation in those affected by craniofacial abnormalities.人类胚胎发育过程中的图案形成缺陷常导致颅面畸形（craniofacial abnormalities）。构建颅面复合体的基因调控程序，大概率受基因间及内含子序列内携带的信息调控。然而，目前尚未有研究系统鉴定出对人类面部形成至关重要的调控序列。本研究针对人类胚胎颅面组织开展了全面的表观基因组注释（epigenomic annotations），并将其与多种组织及细胞类型进行了系统比对。我们鉴定出数千种组织特异性颅面调控序列，以及可能与罕见颅面畸形相关的致病区域。研究表明，在胚胎发育早期活跃的增强子（enhancers）中，与口面裂（orofacial clefting）相关的常见变异呈现显著富集；而与正常面部形态变异相关的变异，则在胚胎发育末期附近出现富集。本研究将相关数据以易于获取的格式公开，以供颅面领域研究人员与临床医生使用，助力未来针对颅面畸形患者非编码变异（non-coding variation）的实验设计与结果解读。