Research

In recent work, we explored the regulatory mechanisms driving expression of an important developmental transcription factor called SOX9 whose perturbation causes craniofacial dysmorphology (Long et al, 2020). We identified clusters of extreme long-range enhancers located over a million base pairs upstream of the SOX9 gene that are active in progenitors of the face (called cranial neural crest cells, CNCCs), exhibit features of synergistic gene regulation and whose ablation recapitulates aspects of a human craniofacial disorder. We are now interested to explore how these clustered enhancers work together to regulate gene expression at long-range.

• Long HK, Osterwalder M, Welsh IC, Hansen K, Davies JOJ, Liu YE, Koska M, Adams AT, Aho R, Arora N, Ikeda K, Williams RM, Sauka-Spengler T, Porteus MH, Mohun T, Dickel DE, Swigut T, Hughes JR, Higgs DR, Visel A, Selleri L, Wysocka J. 2020. Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder. Cell Stem Cell.
• Long HK, Prescott SL and Wysocka J. 2016. Ever-changing landscapes: transcriptional enhancers in development and evolution. Cell, 167(5):1170-1187

We have recently identified regulatory elements at the SOX9 locus, that we termed “stripe-associated structural elements” that shape 3D chromatin structure and play an important role in the long-range control of gene expression in CNCCs (Chen, Long et al, 2023). CTCF binding at these structural elements mediates compaction of the locus, facilitating enhancer-promoter proximity and robust gene expression. To further explore the role of local chromosomal folding in gene regulation, we plan to explore the function of these structural elements using genetic engineering, genomics, bioinformatics, and chromosomal imaging methods. Together, exploration of this new class of regulatory element will uncover how widespread structural elements are in gene regulation, relevant to the interpretation of human genetic disease.

• Chen LF*, Long HK*, Park M, Swigut T, Boettiger AN, Wysocka J (* co-first author). 2023 Structural elements facilitate extreme long-range gene regulation at a human disease locus. Mol Cell

We are interested in human development, evolution and disease, and so much of our research utilises cell-based models that allows us to mimic early human development. We derive facial progenitor cells in the dish, called cranial neural crest cells (CNCCs). These transient embryonic cells retain stem cell-like properties and are able to differentiate into many cell-types that give rise to the face during development, including sensory neurons, glia, connective tissue, and many of the bones and cartilage in the face. We are excited to develop more complex in vitro human models of facial development.

We also use animal models where appropriate to map patterns of enhancer activity and assess phenotypic consequences of regulatory perturbations.