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Cleft Palate Study Shows Transcription Factor, Enhancer Roles in Related Developmental Processes

NEW YORK (GenomeWeb) – A team from the University of Pennsylvania and the University of Bonn has used epigenomics sequencing, genome-wide association study meta-analyses, and other approaches to identify new candidate causal variants for cleft lip and palate, a relatively common birth condition marked by partial or missing cell fusions between an infant's mouth and face cell.

Using available GWAS data — alongside data from chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA sequencing — the researchers profiled transcription factor binding, active enhancers, open chromatin patterns, and gene expression in a human dermal fibroblast cell line containing an inducible p63 variant implicated in cleft lip and palate.

Their findings, published online today in Science Advances, highlighted processes suspected of contributing to cleft lip and palate formation based on enhancer interactions with p63, a transcription factor known for its epidermal development role. Those results lined up with GWAS results pointing to cleft lip and palate-associated variants in some of the same enhancers, they noted.

"[W]e found that many of the genes that are highly associated with clefting are located near the enhancer regions that work with p63," first author Enrique Lin-Shiao, a doctoral student in senior author Shelley Berger's lab in the University of Pennsylvania cell, developmental biology, and epigenetics departments, said in a statement. "This gives us brand new insight into the mechanisms that could lead to disease."

"We show that p63 can establish craniofacial enhancers to regulate downstream genes and that this process is disrupted when p63 carries mutations derived from human disease," Lin-Shiao, Berger, and co-authors wrote, noting that "our results show a novel mechanism underlying pathogenic p63 mutations, in which failure to open and establish enhancers leads to transcriptional dysregulation."

The team noted that although p63 alterations have been implicated in some cleft lip and palate cases, mutations in the p63-coding gene are rarer than cleft lip or cleft palate diagnoses, which appear to stem from both genetic and environmental factors.

In an effort to tease out p63 contributions to cleft lip and palate, the researchers relied on p63 ChIP-seq, H3K27 acetylation ChIP-seq, ATAC-seq-based chromatin accessibility profiles, and RNA-seq in CRL-2522 human dermal fibroblast cells with an inducible version of p63, considering results from those assays alongside genomic data generated at the University of Bonn for individuals with cleft lip and palate.

Their results suggested that p63 binding corresponded with the conversion from closed to open chromatin at a significant subset of the sites involved. That, in turn, appeared to prompt widespread enhancer changes, decreased expression for nearly 1,500 genes, and enhanced expression of some 1,960 genes, including representatives from interferon, inflammation, and immune pathways.

In a series of follow-up experiments, the team further teased out p63's role in the transition between fibroblast and keratinocyte-like epithelial cells, and demonstrated the craniofacial consequences of specific cleft lip and palate-related mutations in p63.

"Our results reveal p63 establishment of enhancers, displaying increased chromatin accessibility and de novo H3K27 acetylation at critical craniofacial genes, and demonstrate that substitution mutations in p63 abrogate this function," the authors reported.

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