High Resolution Epigenomic Atlas of Human Embryonic Craniofacial Development

Abstract

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.

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21

“…All associated variants below a suggestive level of significance (p<1.0e-05) were located within the PDE9A gene, which does not have any known role in controlling risk to OFCs. However, the PDE9A gene overlaps a super-enhancer region for craniofacial development identified from histone profiling in early human craniofacial development (25). Multiple genes in the region, including PDE9A , appear to be actively transcribed during human craniofacial development (Figure 2).…”

Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

“…Multiple patients with varying phenotypes and different insertions at this locus have been described [1][2][3][4][5]. The inserted fragment from chr9 contains multiple enhancers, including two previously described super-enhancer clusters (highlighted by red boxes), that are active in human (Palate (H), Carnegie stage 13) and mouse (Palate (M), embryonic day 11.5) craniofacial development and human cultured cranial neural crest cells (cNCC) [6][7][8]. The inserted enhancers may disturb the normal expression of the SOX3 gene and/or the surrounding genes, which may have led to the cleft palate phenotype in this patient.…”

BIOLOGICAL SCIENCES: Genetics

“…4C-seq was carried out as described (46) using nuclei harvested from approximately 2 million formaldehyde-fixed and glycine-quenched iPSCs and iPSC-derived neurons. NlaIII enzyme was used for the first digestion, and DpnII was used for the second digestion.…”