Enhancer Loss and Gene Dosage Sensitivity Drives a Human Craniofacial Disorder - Dr Hannah K. Long, Sir Henry Wellcome Fellow, Stanford University, CA, USA

Biography:  Dr Hannah Long is a Sir Henry Wellcome post-doctoral research fellow in the laboratory of Professor Joanna Wysocka at Stanford University. Hannah received her undergraduate education at the University of Cambridge in the Natural Sciences, and was awarded her DPhil at the University of Oxford Biochemistry Department in 2014 as a student in the Wellcome Trust Graduate Programme in Chromosome and Developmental Biology. During her PhD, Hannah worked with Professor Rob Klose to uncover conservation of non-methylated islands across vertebrate species and interrogate DNA sequence features that contribute to DNA methylation status. In her post-doctoral work, Hannah has investigated mechanisms of developmental gene regulation, with a focus on long-range enhancer function in craniofacial development, evolution and disease.

Abstract: SOX9 is an important developmental transcription factor which plays pleiotropic roles during embryogenesis. Heterozygous mutations in the SOX9 gene cause a severe congenital disorder called campomelic dysplasia (CD) associated with skeletal dysplasia, XY sex reversal, and dysmorphic facial features. Interestingly, distinct non-coding mutations within a large gene desert surrounding the SOX9 gene recapitulate specific subsets of CD phenotypes, suggesting ablation of tissue-specific regulatory elements. One class of patients with an anomaly called Pierre Robin sequence (PRS), characterised by hypoplastic lower jaw and cleft palate, have deletions over a megabase upstream of the SOX9 gene. Within this deletion region, we identify extreme long-range enhancers that mediate cranial neural crest-specific SOX9 expression at distances of up to 1.5 Mb away from the promoter. Activity of a subset of these human craniofacial enhancers is conserved in the mouse, and we investigate the impact of conserved enhancer deletion on mouse craniofacial skeletal development. Overall, we characterize the longest-range human enhancers involved in congenital malformations, provide molecular insights into disease aetiology to directly classify PRS as an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.