Gene Enhancers Influence Your Unique Identity

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Genes and enhancers govern your looks. Image by Sfmontyo.

Your unique face is your identity and allows society to identify you. Even when twins have faces which look very similar, the genes and gene networks underlying the facial morphology are quite distinct. The complex array of regulatory elements that work together to form one’s skull and facial morphology renders the studies of birth defects associated with facial structures very difficult.

An integral component of gene regulatory machinery, gene enhancers contribute significantly, behind the scenes, to create the specific looks you possess. Co-activator proteins bind these DNA sequences and serve to recruit other proteins to promoters to drive gene transcription.

Enhancers are in regions between genes, far away (~ several kb) from the genes they control. One or more enhancers could also act together, to control gene expression. Depending on the need of the hour, in a cell, specific enhancers loop across several bases of DNA, to interact with the gene promoters they control.

Genome-Wide Analysis of Enhancers in Mice

Given their significance, one would expect enhancers to be conserved across species, and that is exactly what Dr. Visel’s group reported in their most recent Science article. Dr. Visel’s group explored the role of enhancers in the development of facial muscles in mice and found an astounding 96% of enhancers similar across the two organisms. Given the conservation of DNA sequence between humans and mice, the study assumes that the candidate enhancers play similar roles in controlling important genes pivotal for skull and face development in mice and humans.

Dr. Visel’s group utilized a protein, p300, that is commonly bound to enhancers, to identify ~ 4400 enhancers, that could potentially play a role in skull and face development in e11.5 day mouse embryos.  In order to first prove that these DNA sequences identified as enhancers could indeed increase activity of gene expression, ~200 selected enhancers were each placed next to a promoter that drives a reporter gene and injected into mice embryos. 120 of 200 validated as truly enhancing the activity of the reporter gene.

Previous genome-wide enhancer studies in mice added 75 additional enhancers to the repertoire of the craniofacial discovery enhancers. Through high-resolution 3D mapping of whole embryos, the authors were able to validate ~55 enhancers affecting gene expression in specific regions of the face, like enhancers mm933 and mm426 activate target genes in the nose.

Diverse Roles of  Enhancers in Craniofacial Defects

Depending on the cellular context, it is common to find more than one enhancer controlling a specific gene’s transcription. In these cases, its hard to associate any one particular enhancer with specific genes. Just imagine several beads, numbered one to five on a string, and now, if we wish to bring bead one near bead four, we would have to loop over bead two and three to do so. Similarly, in the case of enhancers, active enhancers have been seen to loop over inactive enhancers and large DNA sequences to come in contact with the target gene promoter. Dr.Visel’s group was able to demonstrate the workings of complex combinations of enhancers to fine tune gene expression in the skull and face.

Enhancers loop around promoters to effect gene transcription. Image by Kelvinsong.

Enhancers loop around promoters to effect gene transcription. Image by Kelvinsong.

Dr. Visel in his interview with Decoded Science explained thus: “Many genes and gene pathways required for normal craniofacial development are implicated in craniofacial birth defects. We demonstrated role of potential enhancers in genomic regions associated with increased risk for cleft palate in humans.”

Deletion of Enhancers Alters Craniofacial Development

The gold standard assay to emphasize the importance of enhancers is to delete the specific enhancer and generate mouse embryos, and subsequently assess if any alteration in cranial and facial development is seen. The authors conducted these knockdown studies on three candidate enhancers, and two of three showed significant, but not pathological cranial and facial alterations in the deleted enhancer mice compared to normal mice at 8 weeks of age.

Researchers have performed only 3 enhancer knockdown studies, it is early to suggest that enhancers affect craniofacial morphology in subtle ways, unlike the serious pathological effects caused by protein-coding mutations. But expanding these studies to other candidate enhancers will conclusively answer that question.

Dr. Visel further adds that various methodologies exist for mapping enhancers, and each have their limits on sensitivity and specificity, so their future studies would involve the utilization of the other epigenomic methods as well, in order to build a comprehensive map of enhancers required for normal face and skull development.

Resources

Attanasio C, Nord AS, Zhu Y, Blow MJ, Li Z, Liberton DK, Morrison H, Frick IP, Holt A, Hosseini R, Phouanenavong S, Akiyam JA, Shoukry M, Afzal V, Rubin EM, Fitzpatrick DR, Ren B, Hallgrimsson B, Pennacchio LA and Visel A. Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers. (2013). Science. Accessed November 3, 2013.

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