Gene regulation in human craniofacial development and disease. Following undergraduate studies at the University of Cambridge, Hannah followed her interests in genome and developmental biology to conduct her doctoral work at the Department of Biochemistry, University of Oxford. During her DPhil, Hannah worked with Professors Rob Klose and Roger Patient where she discovered that non-methylated islands of DNA are a conserved feature of vertebrate genomes and investigated DNA sequence features that contribute to DNA methylation status.For her postdoc, Hannah was awarded a Sir Henry Wellcome post-doctoral research fellowship and worked with Professor Joanna Wysocka at Stanford University in collaboration with Professors Doug Higgs and Jim Hughes at the University of Oxford. Hannah utilised human embryonic stem cell and murine models to functionally characterise gene regulatory regions, called enhancers, that are perturbed in patients with an isolated craniofacial disorder called Pierre Robin sequence (PRS). Hannah Long Hannah started as a Programme Leader Track (PLT) Group Leader at the MRC Human Genetics Unit in 2021. Hannah’s group leverages an in-depth knowledge of the SOX9 regulatory locus and developmental model systems to investigate how combinatorial enhancer action and 3D genome architecture contribute to gene regulation. Work in Hannah’s group will have important implications for understanding how non-coding genetic variation can impact normal-range human facial development and can contribute to disease. Long Lab Website Lab members Dr Kirsty Uttley, Dr Nicola Carruthers, Carlo De Angelis, Kasia Milto, Verena Obermüller, Ewa Ozga, Hannah Jüllig, and Kun Wu. Research How multicellular organisms, with their elaborate pattern and diverse array of cell-types, arise during development from a single cell is a fascinating and complex process. Given that all cells in a developing human embryo share the same genome, differential utilisation of a limited set of genes is key for driving the observed cellular diversity. To orchestrate cell-type specific patterns of gene expression, non-coding regulatory elements called enhancers act as regulatory switches, turning genes on and off in time and space during development. Our lab investigates mechanisms of gene regulation in the context of craniofacial development, and how enhancer perturbation can lead to human congenital craniofacial disorders.The vertebrate face largely develops from a transient embryonic cell-type called the cranial neural crest. To study human facial development, we utilise both in vitro differentiation of human embryonic stem cells to cranial neural crest cells (CNCCs) and animal models coupled with genome-editing, epigenomic analysis and imaging-based approaches. In recent work, we focused on understanding the regulatory mechanisms driving expression of an important developmental transcription factor called SOX9 whose perturbation causes craniofacial dysmorphology. We identified clusters of extreme long-range enhancers over a million base pairs upstream of the SOX9 gene that are active in CNCCs, exhibit features of synergistic gene regulation and whose ablation recapitulates aspects of a human craniofacial disorder.Leveraging this interesting regulatory domain, we are now investigating how chromosomal structure relates to gene activity using genetic engineering and imaging approaches. We are also investigating how multiple enhancers act in combination both within clusters of enhancers and across a regulatory locus, and are seeking to identify sequence features and position effects that influence enhancer combinatorial behaviour. Ultimately our work will further our understanding of enhancer function during normal development and help us to predict how non-coding genetic mutations may impact developmental gene expression and drive disease phenotypes. Image Selected publications Uttley K*, Jüllig HJ*, De Angelis C, Auer JMT, Ozga E, Bengani H, Long HK‡ (* co-first author; ‡ corresponding author). Neanderthal-derived variants increase SOX9 enhancer activity in craniofacial progenitors that shape jaw development. Development (2025) 152, dev204779 – accepted (bioRxiv)Chen LF*, Long HK*, Park M, Swigut T, Boettiger AN‡, Wysocka J‡ (* co-first author; ‡ co-corresponding author). Structural elements promote architectural stripe formation and facilitate ultra-long-range gene regulation at a human disease locus. Molecular Cell 83 (9):1446-1461 (2023).Chen LF, Long HK. Topology regulatory elements: from shaping genome architecture to gene regulation. Current Opinion in Structural Biology. 4:83:102723 (2023). Long HK, Osterwalder M, Welsh IC, Hansen K, Davies JOJ, Liu Y, Koska M, Adams AT, Aho R, Arora N, Ikeda K, Williams R, Sauka-Spengler T, Porteus M, Mohun T, Dickel DE, Swigut T, Hughes JR, Higgs DR, Visel A, Selleri L, Wysocka J. Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder. Cell Stem Cell 27, 1–19 (2020).Long HK*, Prescott SL*, Wysocka J (* co-first author). Ever-Changing Landscapes: Transcriptional Enhancers in Development and Evolution. Cell 167(5): 1170–1187 (2016). This article was published on 2026-04-23
