Grainyhead-like Transcription Factors in Craniofacial Development

Abstract

Craniofacial development in vertebrates involves the coordinated growth, migration, and fusion of several facial prominences during embryogenesis, processes governed by strict genetic and molecular controls. A failure in any of the precise spatiotemporal sequences of events leading to prominence fusion often leads to anomalous facial, skull, and jaw formation-conditions termed craniofacial defects (CFDs). Affecting approximately 0.1% to 0.3% of live births, CFDs are a highly heterogeneous class of developmental anomalies, which are often underpinned by genetic mutations. Therefore, identifying novel disease-causing mutations in genes that regulate craniofacial development is a critical prerequisite to develop new preventive or therapeutic measures. The Grainyhead-like ( GRHL) transcription factors are one such gene family, performing evolutionarily conserved roles in craniofacial patterning. The antecedent member of this family, Drosophila grainyhead ( grh), is required for head skeleton development in fruit flies, loss or mutation of Grhl family members in mouse and zebrafish models leads to defects of both maxilla and mandible, and recently, mutations in human GRHL3 have been shown to cause or contribute to both syndromic (Van Der Woude syndrome) and nonsyndromic palatal clefts. In this review, we summarize the current knowledge regarding the craniofacial-specific function of the Grainyhead-like family in multiple model species, identify some of the major target genes regulated by the Grhl transcription factors in craniofacial patterning, and, by examining animal models, draw inferences as to how these data will inform the likely roles of GRHL factors in human CFDs comprising palatal clefting. By understanding the molecular networks regulated by Grhl2 and Grhl3 target genes in other systems, we can propose likely pathways that mediate the effects of these transcription factors in human palatogenesis.

The transcription factor Grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes

“…In ovarian cancer for example, GRHL2 expression counteracts epithelial to mesenchymal transition and increases the overall survival of patients 59 , 60 . Mutations in the GRHL factors are also linked to pulmonary fibrosis 66 and several craniofacial disorders 67 . We found that mammalian GRHL homologs are required for setting up the accessible epithelial chromatin landscape, and that the biochemistry of GRHL binding and nucleosome displacement are highly analogous to Drosophila .…”

Wnt signaling in orofacial clefts: crosstalk, pathogenesis and models

“…Exome sequencing-based association studies have revealed several variations in human GRHL3 associated with non-syndromic CPO in almost all populations studied (Leslie et al, 2016; Mangold et al, 2016; Hoebel et al, 2017; Eshete et al, 2018) (Table 2), except in the Han Chinese (He and Bian, 2016), suggesting GRHL3 as a strong candidate gene for non–syndromic CPO. Thus, proper Grhl3 expression in the epithelium during palatogenesis seems to be crucial for normal palate formation (Carpinelli et al, 2017). In mice, a cooperative interaction has been suggested between Grhl2 and Grhl3 during primary neurulation (Box 1) (Rifat et al, 2010), and Grhl3 might act downstream of canonical Wnt signaling during neural tube closure (Kimura-Yoshida et al, 2015).…”

Leveraging Family History in Case-Control Analyses of Rare Variation

“…4). GRHL2 is in the same gene family as GRHL3, which is a transcription factor that causes syndromic forms of clefting and is associated with nonsyndromic clefting in other GWAS (Leslie et al, 2016a,b; Carpinelli et al, 2017; Peyrard-Janvid et al, 2014).…”

“…Applying our method to Pittsburgh Orofacial Cleft Multiethnic GWAS (Leslie et al, 2016a,b), we identified a gene (GRHL2) (not previously reported) to suggestively associate with cleft lip and palate phenotypes. GRHL2 is in the same gene family as GRHL3, which is a transcription factor that causes in syndromic forms of clefting and was found to be associated with nonsyndromic clefting in GWAS (Leslie et al, 2016a,b; Carpinelli et al, 2017; Peyrard-Janvid et al, 2014). Burden and SKAT on these same phenotypes (figure 4) failed to identify any significant or suggestive genes.…”