Contact information
| adam.handel@ndcn.ox.ac.uk |
Figure 1 Stem-cell derived cortical neurons
(a) Immunofluorescence microscopy images showing TUJ1 (green) and TBR1 (red), scale bar = 50µm; (b) Principal component analysis of single cell RNA-seq data from iPSC-derived cortical neurons (black), iPSCs (red), neural progenitors (yellow), fetal radial glia (green), fetal newborn cortical neurons (blue), fetal matured cortical neurons (purple) showing that iPSC-derived cortical neurons closely resemble primary human fetal neurons. Comparison data from Pollen et al. (PMID 25086649).
Adam Handel
NIHR Clinical Lecturer
Current Research
During my Clinical Lectureship, I will be using functional genomics methods to understand neuroimmunological conditions. My particular focus will be on applying recently developed single cell genomics approaches to immune-mediated demyelinating diseases, such as neuromyelitis optica and multiple sclerosis.
Single cell methods are ideally suited for studying the biology of extremely heterogeneous populations of cells, as exemplified by T-cells in the case of autoimmunity; these provide read-outs of cellular functions in individual cells rather than averaging over a large number of cells. This will enable me to identify novel mechanisms of disease.
I am also continuing collaborative projects, started during my DPhil, which aim to uncover the epigenomic basis of promiscuous gene expression in the thymus with Prof. Holländer and further explore the use of stem cell-derived systems to model neurological disease with Prof. Cader.
Previous Research
Induced pluripotent stem cells (iPSC) offer a non-invasive method of modelling human neurological disease in a dish. We used single cell transcriptomics to demonstrate that iPSC-derived cortical neurons closely resemble primary human fetal neurons (Fig. 1). However, I found that markers used to allocate neurons to specific layers within the cortex do not work well in these cells. This suggested that, although a powerful model of corticogenesis, care should be taken in interpreting findings from iPSC-derived systems.
Thymic epithelial cells (TEC) act as vital gatekeepers within the adaptive immune system. Thymocytes are screened by TEC to ensure that only those cells that have the potential to bind to foreign proteins but not proteins found naturally within the organism survive selection and to form the peripheral T-cell repertoire. In order for this to take place, TEC must express almost every protein found in any tissue around the body within the confines of the thymus. We applied functional genomics methods to study the function of TEC within the mature thymus and particularly the role of Foxn1, a master regulator of thymic development and function. Our work identified, for the first time, a set of genes directly regulated by Foxn1 that were critical in supporting the normal function of the thymus (Fig. 2).
I have also examined the contribution of genetic and environmental risk factors to multiple sclerosis susceptibility, including the major histocompatibility complex (MHC), vitamin D deficiency, smoking and Epstein-Barr virus. We used functional genomics methods to identify the location of vitamin D receptor binding across the genome and showed that this was closer to variants associated with multiple sclerosis than expected by chance.
Key Publications
5-
Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells.
Žuklys S. et al, (2016), Nat Immunol, 17, 1206 - 1215
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Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics.
Handel AE. et al, (2016), Hum Mol Genet, 25, 989 - 1000
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Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease.
Handel AE. et al, (2013), BMC Med, 11
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Genetic and environmental factors and the distribution of multiple sclerosis in Europe.
Handel AE. et al, (2010), Eur J Neurol, 17, 1210 - 1214
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Environmental factors and their timing in adult-onset multiple sclerosis.
Handel AE. et al, (2010), Nat Rev Neurol, 6, 156 - 166
Recent Publications
5-
Most brain disease-associated and eQTL haplotypes are not located within transcription factor DNase-seq footprints in brain.
Handel AE. et al, (2017), Hum Mol Genet, 26, 79 - 89
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Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells.
Žuklys S. et al, (2016), Nat Immunol, 17, 1206 - 1215
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Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics.
Handel AE. et al, (2016), Hum Mol Genet, 25, 989 - 1000
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Bioinformatics Analysis of Estrogen-Responsive Genes.
Handel AE., (2016), Methods Mol Biol, 1366, 29 - 39
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EBNA2 binds to genomic intervals associated with multiple sclerosis and overlaps with vitamin D receptor occupancy.
Ricigliano VA. et al, (2015), PLoS One, 10
Figure 2 Novel Foxn1 gene targets
(a) Foxn1 ChIP-seq binding profiles in TEC around two novel Foxn1 gene targets, Psmb11 and Cd83, which are critical in thymopoiesis. (b) Relative expression of Psmb11 and Cd83 after doxycyline-induced excision of Foxn1 in TEC.