The Merkle laboratory studies the molecular and cellular basis of human disease, in particular obesity and the sleep disorder narcolepsy. Obesity and narcolepsy are both associated with the aberrant function of specific neurone types in the hypothalamus, an evolutionarily ancient brain region that regulates essential physiological and behavioural processes. I recently developed a method to generate the relevant hypothalamic neurone populations from human pluripotent stem cells (Merkle et al., Development, 2015). Our laboratory uses a range of cutting edge techniques to elucidate disease mechanisms including: directed differentiation of human stem cells, genome engineering, optogenetics, high content imaging, transcriptomics, and animal models. Our two main projects are:
Many mutations that cause obesity are known, but the mechanisms by which they cause disease are poorly understood. We are using genetic and pharmacological approaches to test the hypothesis that certain mutations cause obesity by affecting the function of hypothalamic neurones that regulate feeding behaviour. This work is being carried out in collaboration with Prof. Sir Steve O’Rahilly and Prof. Sadaf Farooqi.
Normal DNA methylation is essential for proper development and cellular function. Specific point mutations in the DNA methltransferase DNMT1 lead to progressive neurodegenerative diseases, one of which is characterised by early-onset narcolepsy. The mechanism by which aberrant methylation leads to the loss of specific neurone types is being pursued biochemically as well as in genome-edited stem cells and mouse models.
Outstanding postdoctoral candidates interested in joining our team are encouraged to write Dr. Merkle directly at email@example.com.
1) Merkle FT, Neuhausser WM, Santos D, Valen E, Gagnon JA, Maas K, Sandoe J, Schier AF, Eggan K. Efficient CRISPR-Cas9-mediated generation of knockin human pluripotent stem cells lacking undesired mutations at the targeted locus. Cell Rep. 2015 May 12;11(6):875-83. doi: 10.1016/j.celrep.2015.04.007.
2) Merkle FT, Maroof A, Wataya T, Sasai Y, Studer L, Eggan K, Schier AF. Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells. Development. 2015 Feb 15;142(4):633-43. doi: 10.1242/dev.117978.
3) Merkle FT, Eggan K. Modeling human disease with pluripotent stem cells: from genome association to function. Cell Stem Cell. 2013 Jun 6;12(6):656-68. doi:10.1016/j.stem.2013.05.016.
4) Merkle FT, Mirzadeh Z, Alvarez-Buylla A. Mosaic organization of neural stem cells in the adult brain. Science. 2007 Jul 20;317(5836):381-4.