“Our goal is to understand the molecular basis of cell identity, and the transcriptional control mechanisms that determine diversity in cell fate choice throughout the body plan”
Studying the molecular mechanisms that control cell fate decisions
As an embryo develops, pluripotent cells develop into a wide variety of mature cell types along the length of the body. This diversity is dependent on position: some cell types form exclusively in the head, while others develop in the trunk. We have developed insight into how differences in the body plan emerge in the nervous system, where visceral motor neurons are positioned at cranial levels, contrasting with spinal motor neurons that develop at caudal positions. These differences in cell identity are dependent on the activity of a vast array of non-coding regulatory elements in the genome, often termed enhancers, that are fundamental to controlling gene activity.
Our ambition is to define the molecular principles that determine cell type identity and diversity during development, by asking:
How do different cell types emerge in different parts of the nervous system?
How do regulatory elements control cell identity and future lineage decisions?
How can we exploit these molecular principles to engineer specific cell types in vitro from pluripotent cells?
By developing strategies to engineer precise tissues from embryonic stem cells, it is our hope that we will contribute valuable insights for regenerative medicine and the future of disease modelling.
We are taking a tissue engineering approach, using embryonic stem cells to generate defined cell types in vitro, benchmarked against their in vivo counterparts using mouse genetic approaches. This allows us to examine which signals direct cell fate decisions during development, and dissect how this is controlled at the molecular level, by leveraging genomic and proteomic approaches.
By combining computational biology with experimental manipulations, we are developing insight into how regulatory elements function, in the control of competence and cell identity.
Vicki Metzis holds a Sir Henry Dale Fellowship at Imperial College London.
Imperial profile: https://www.imperial.ac.uk/people/v.metzis
Exelby K, Herrera-Delgado E, Garcia Perez L, Perez-Carrasco R, Sagner A, Metzis V, Sollich P, Briscoe J. (2021) Precision of Tissue Patterning is Controlled by Dynamical Properties of Gene Regulatory Networks. Development 148 (4): dev197566.
Semprich CI, Metzis V, Patel H, Briscoe J, Storey KG (2019). ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex. bioRxiv 2019;586719.
Metzis V, Steinhauser S, Pakanavicius E, Gouti M, Stamataki D, Ivanovitch K, Watson T, Rayon T, Mousavy Gharavy SN, Lovell-Badge R, Luscombe NM, Briscoe J. (2018). Nervous System Regionalization Entails Axial Allocation before Neural Differentiation. Cell;175(4):1105-1118.e17
Gabrysova L, Alvarez-Martinez M, Luisier R, Cox LS, Sodenkamp J, Hosking C, Perez-Mazliah D, Whicher C, Kannan Y, Potempa K, Wu X, Bhaw L, Wende H, Sieweke MH, Elgar G, Wilson M, Briscoe J, Metzis V, et al. (2018). c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells. Nature Immunology;19(5):497-507.
Lu H, Galeano MCR, Ott E, Kaeslin G, Kausalya PJ, Kramer C, Ortiz-Bruchle N, Hilger N, Metzis V, Hiersche M, et al. (2017). Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nature Genetics;49(7):1025-1034
Gouti M, Metzis V, Briscoe J. (2015). The route to spinal cord cell types: a tale of signals and switches. Trends Genet;31(6):282-9.
Metzis V, Courtney AD, Kerr MC, Ferguson C, Rondon Galeano MC, Parton RG, Wainwright BJ, Wicking C. (2013). Patched1 is required in neural crest cells for the prevention of orofacial clefts. Human Molecular Genetics;22:5026-5035
Butterfield NC, Metzis V, McGlinn E, Bruce SJ, Wainwright BJ, Wicking C. (2009). Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Development;136: 3515-3524