A new study explains, at least in part, the incredibly subtle ways each face is unique. The study points to the role played by transcriptional enhancers, regulatory sequences that activate or amplify the expression of specific genes, in craniofacial development.
To delve deeply into the genomic basis of craniofacial development, researchers at the Lawrence Berkeley National Laboratory used a combination of epigenomic profiling, in vivo characterization of candidate enhancer sequences in transgenic mice, and targeted deletion experiments. (According to the researchers, most of the enhancer sequences that were identified and mapped in the study are at least partially conserved between humans and mice.)
The scientists were especially keen to examine the role of distant-acting enhancers. In previous studies, the scientists had studied distant-acting gene enhancers in the heart, the brain, and other organ systems. Such enhancers, they found, could regulate their targets from across distances of hundreds of thousands of base pairs.
The scientists were also aware that enhancers often control the expression of their target genes in a modular fashion, where different enhancers activate the expression of the same gene in different cell types, anatomical regions, or at different developmental time points. In principle, such complex arrays of enhancers acting on individual genes could fine-tune distinct aspects of gene expression in different developmental processes, which in turn could affect specific phenotypic traits including facial shape.
The scientists describe the results of their facial investigation in the October 25 issue of Science in a paper entitled “Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers.” In this paper, the authors write: “Throughout the genome, we identified several thousand sequences that are likely to be distant-acting enhancers active in vivo during mammalian craniofacial development.” Expanding on this point, the paper’s lead author, Catia Attanasio, Ph.D., said that the study revealed “complex regulatory landscapes, consisting of enhancers that drive spatially complex developmental expression patterns.”
Reflecting on all this complexity, the study’s leader, geneticist Axel Visel, Ph.D., added, “We don’t know yet what all of these enhancers do, but we do know that they are out there and they are important for craniofacial development.”
In all, the scientists identified more than 4,000 candidate enhancer sequences predicted to be active in fine-tuning the expression of genes involved in craniofacial development, and created genome-wide maps of these enhancers by pinpointing their location in the mouse genome. The researchers also characterized in detail the activity of some 200 of these gene enhancers and deleted three of them. Analysis of mouse lines in which individual craniofacial enhancers had been deleted revealed significant alterations of craniofacial shape, demonstrating the functional importance of enhancers in defining face and skull morphology.
Besides adding to our understanding of the connection between genetics and craniofacial shape, the scientists write, their study provides a functional genomic framework for the analysis of craniofacial birth defects. And so, the scientists hope, their work may build on previous studies that found partial overlap between loci involved in normal facial shape variation and in craniofacial birth defects, supporting the possibility that some dysmorphologies represent the extreme ends of the normal spectrum of variation.