"My lab is focused on finding out how epigenetics regulates biological mechanisms in health and during disease. I believe greater understanding here will be an important step in identifying targeted treatments for brain disorders in the future." Sarah Marzi
UK DRI Emerging Leader
Having graduated with degrees in mathematics and psychology from the University of Freiburg, Dr Sarah Marzi completed her PhD in complex disease epigenetics with Prof Jonathan Mill at King’s College London and worked as a postdoctoral researcher with Prof Vardhman Rakyan at Queen Mary University of London. At the end of 2019, she established an independent research group as an Edmond and Lily Safra Research Fellow, joining the UK DRI at Imperial. The Marzi lab combines experimental genomic and epigenomic techniques with innovative statistical and computational analyses to understand gene regulatory mechanisms contributing to the earliest stages of neurodegenerative disease. Dr Marzi became a UK DRI Emerging Leader in 2021, sponsored by Centre Director Prof Paul Matthews.
1. At a glance
The likelihood of someone developing dementia is influenced by a combination of their genetics and the environment they are exposed to. However, it is not clear how these factors interact with each other to affect cells in the brain. One possible mechanism is through epigenetics – chemical modifications to the genetic material in cells that regulate gene expression.
Dr Sarah Marzi aims to determine the role of epigenetic regulation in neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease, using state of the art epigenetic and genomic techniques in cell populations and at the single cell level. Dr Marzi’s research has the potential to identify an epigenetic link between genetic and environmental risk in dementia and identify mechanisms by which these risk factors make cells susceptible to neurodegeneration. The aim of this research is to reveal opportunities and avenues for new therapies for neurodegeneration and dementia.
2. Scientific goals
While it is known that genetic variants and environmental factors contribute to the risk of developing neurodegenerative diseases, the biological mechanisms involved remain largely unknown. An emerging area of interest is the study of how these factors affect epigenetic processes, a collection of biochemical mechanisms that regulate the levels, location and timing of gene expression.
Dr Sarah Marzi is an expert in epigenetic regulation, particularly in relation to human disease. She has expertise in advanced sequencing techniques, including those sensitive to epigenetic modifications, working with human brain tissue as well as in vivo and in vitro model systems. Dr Marzi combines these experimental techniques with innovative statistical and computational analytical methods in her research.
In her UK DRI programme, Dr Marzi is studying functional epigenetic pathways and mechanisms in Parkinson’s and Alzheimer’s diseases. One of Dr Marzi’s core interests lies in the immune cells of the brain. There is growing evidence that disease-associated microglia states play an important role in how genetic variants influence Alzheimer’s disease. In her programme, Dr Marzi aims to identify the upstream regulatory mechanisms that control microglia state transitions and observed gene-environment interactions.
Evidence also suggests that certain environmental factors, particularly several types of agricultural pesticide, can increase the risk of Parkinson’s disease. As the mechanisms via which these environmental risk factors act on disease are not clear, Dr Marzi is investigating how epigenetic processes may be playing a role.
Main objectives and research goals:
1. Determine how gene regulation is altered in specific disease-relevant cell types in an environmentally-induced Parkinson’s disease model.
2. Identify where the earliest molecular changes occur.
3. Determine cell-type specific vulnerabilities to exposure to the pesticide rotenone.
4. Identify how non-coding genetic risk variants relate to environment-driven regulatory changes.
3. Team Members
Dr Di Hu (Postdoctoral Researcher)
Maria Tsalenchuk (PhD student)
Kitty Murphy (PhD student)
Within UK DRI:
- Dr Alexi Nott, UK DRI at Imperial
- Prof Bart De Strooper, UK DRI at UCL
- Dr Nathan Skene, UK DRI at Imperial
- Prof Paul Matthews, UK DRI at Imperial
Beyond UK DRI:
- Dr Emily Rocha, University of Pittsburgh
- Dr Javier Alegre, Imperial College London
- Prof Jonathan Mill, University of Exeter
- Prof Leonard Schalkwyk, University of Essex
- Dr Renzo Mancuso, VIB Antwerp
- Prof Simone Di Giovanni, Imperial College London
- Prof Timothy J Greenamyre, University of Pittsburgh
Parkinson’s disease, Alzheimer’s disease, bioinformatics, biostatistics, epigenetics, histone modifications, chromatin interactions, regulatory genomics, microglia
Genome-wide epigenomic studies, ChIP-seq, CUT&Tag, ATAC-seq, RNA-seq, scRNA-seq, 10x Multiome, DNA methylation array, WGS, nanopore sequencing, bioinformatics, statistical modelling, cell-type deconvolution
7. Key publications
Murphy, KB, Nott, A, Marzi, SJ#. CHAS, a deconvolution tool, infers cell type-specific signatures in bulk brain histone acetylation studies of brain disorders. bioRxiv. 2021
Åsenius, F, Gorrie-Stone, TJ, Brew, A, Panchbaya, Y, Williamson, E, Schalkwyk, LC, Rakyan, VK, Holland, ML, Marzi, SJ*,#, Williams, DJ*. The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations. PLOS Genetics. 2020.
Hannon, E, Marzi, SJ, Schalkwyk, LC, Mill, J. Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains. Molecular Brain. 2019.
Marzi, SJ, Leung, SK, Ribarska, T, Hannon, E, Smith, AR, Pishva, E, Poschmann, J, Moore, K, Troakes, C, Newman, S, Beck, S, Lunnon, K, Schalkwyk, LC, Mill, J. A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nature Neuroscience. 2018.
Marzi, SJ, Sugden, K, Arsenault, L, Belsky, DW, Burrage, J, Corcoran, D, Danese, A, Fisher, HL, Hannon, E, Moffitt, TE, Odgers, CL, Pariante, C, Williams, BS, Wong, CCY, Mill, J, Caspi, A. Analysis of DNA methylation in young people reveals limited evidence for an association between victimization stress and epigenetic variation in blood. American Journal of Psychiatry. 2018.
Hübel, C*, Marzi, SJ*, Breen, G, Bulik, CM. Epigenetics in Eating Disorders – a systematic review. Molecular Psychiatry. 2018.
* Shared first/senior authors #Corresponding author