My group aims to discover the epigenetic changes taking place during cancer initiation and develop potential drugs that can prevent these changes which may be abnormal but reversible, before many damaging mutations occur.
Resetting transcription factor control circuitry towards ground state pluripotency in human. Cell (2014) 58(6): 1254–1269. PMID: 25215486
FGF Signaling Inhibition in ESCs Drives Rapid Genome-wide Demethylation to the Epigenetic Ground State of Pluripotency. Cell Stem Cell (2013) 13(3):351-9. PMID: 23850245
Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single nucleotide resolution in ES cells. Science (2012) 336(6083):934-7. PMID: 22539555
Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature (2011) 473(7347):398-402. PMID: 21460836
There is evidence that cancers can originate from adult stem cells, cells which are present in all our tissues, and are necessary as they regenerate organs following cellular and tissue damage. Adult stem cells, just like embryonic stem cells, have the ability to self-renew (meaning that daughter cells will be clones of the mother cells) or differentiate (give rise to mature cells). Currently, the understanding is that these cells randomly accumulate mutations as we age which will eventually give rise to cancer cells. Generally, this process is a black box and the hope is that future research will bring more clarity to understand how most cancers happen in humans.
We are particularly interested in cellular (re)programming and epigenetics and how these processes can give rise to a large palette of cell identities as well as cancer cells. Epigenetic mechanisms (including DNA methylation, histone modifications and nucleosome positioning) allow genetically identical cells to functionally diversify and, whilst reversible, they are specific for each cell type and have essential roles in reinforcing cellular identity.
Cancer has been associated with epigenetic aberrations (since the 70s) but so far it has been difficult and cumbersome to test whether they undoubtedly alter cellular identity. Recent technological developments allowed researchers to ask this question and untangle epigenetic mechanisms that happen at many loci in the genome. We recently demonstrated, using epigenetic editing with CRISPR technology, that controlled deposition of DNA methylation at the promoter of the tumour suppressor gene CDKN2A allowed primary human cells to successfully bypass senescence (Saunderson et al., Nature Comms 2017 ). These primary cells were obtained from our institute’s tissue bank, from healthy women who have undergone breast reduction mammoplasty. Normally, these cells when cultured in vitro die due to senescence. This was prevented with the help of epigenetics. The implication of this finding is that epigenetic changes can confer selective advantage during cancer evolution and, once deposited, it will be propagated for the benefit of the cancer cell.
One of our ongoing projects aims to identify how such increases in DNA methylation could happen in cells naturally or associated with cancer. Epigenetic analysis of human cancers has revealed widespread promoter hypermethylation alongside global loss of this modification. We are using embryonic stem cells as a model system to elucidate the mechanisms of both processes. Our lab is also interested in the epigenetic changes following overexpression or mutation of a known oncogene. We seek to link signalling processes to epigenetic mechanisms and prevent downstream consequences aiding cancer evolution.
Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors Saunderson EA, Stepper P, Gomm JJ et al. Nature Communications (2017) 8(7)
Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism Hahn O, Grönke S, Stubbs TM et al. Genome Biology (2017) 18(7)
The Ageing Brain: Effects on DNA Repair and DNA Methylation in Mice. Langie SAS, Cameron KM, Ficz G et al. Genes (Basel) (2017) 8(1)
Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. Hore TA, von Meyenn F, Ravichandran M et al. Proc Natl Acad Sci U S A (2016) 113(2) 12202-12207
The Influence of Hydroxylation on Maintaining CpG Methylation Patterns: A Hidden Markov Model Approach. Giehr P, Kyriakopoulos C, Ficz G et al. PLoS Comput Biol (2016) 12(2) e1004905
Resetting Transcription Factor Control Circuitry toward Ground-State Pluripotency in Human. Takashima Y, Guo G, Loos R et al. Cell (2015) 162(2) 452-453
Data resource profile: Accessible resource for integrated epigenomic studies (ARIES) Relton CL, Gaunt T, McArdle W et al. International Journal of Epidemiology (2015) 44(7) 1181-1190
New insights into mechanisms that regulate DNA methylation patterning. Ficz G J Exp Biol (2015) 218(2) 14-20
Genome-wide bisulfite sequencing in zygotes identifies demethylation targets and maps the contribution of TET3 oxidation. Peat JR, Dean W, Clark SJ et al. Cell Rep (2014) 9(2) 1990-2000
Loss of 5-hydroxymethylcytosine in cancer: cause or consequence? Ficz G, Gribben JG Genomics (2014) 104(2) 352-357
I started my research career at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany as a masters student at the first International MSc/PhD Research School in Molecular Biology. Here I had the opportunity to work with exceptional people in various research areas and this inspired me in my work for the years to come.
I came across Epigeneticsearly on and was fascinated by the paradigms and the questions at that time, so in 2002 I decided to do my PhD with Donna Arndt-Jovin working on the Polycomb-group of genes (PcG), which control body patterning in the fruit fly model system. I found that the PcG proteins are extremely dynamic on the genes they control, presumably having the ability to quickly respond to environmental signals in development.
Later on, for my postdoctoral research, I joined the group of Prof. Wolf Reik at the Babraham Institute, University of Cambridge, in 2005 where I worked on Epigenetic reprogramming in the mammalian system. We were seeking to find the elusive mechanism capable of erasing the epigenetic memory in cells. This memory, in the form of a chemical methyl group on the 5’ position of cytosines in the DNA, is essential for normal mammalian development and for maintaining identity of adult cells. Such reprogramming happens at fertilization and in germ cells in order to re-establish totipotency in early embryogenesis. After the discovery of the TET (ten-eleven translocation) protein activity, which oxidises 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), we mapped for the first time the genomic positions where 5hmC is generated in mouse embryonic stem cells and found that indeed this mechanism is in part responsible for removing the repressive 5mC signal in DNA.
In 2013 my research indicated that epigenetic reprogramming is mediated as well by signalling networks, which control the genes involved in maintaining the methylation patterns in cells. This made me understand the relevance of such mechanisms in health and disease therefore I decided to investigate them in adult stem cells which regenerate our body and have direct impact on ageing and cancer. I was appointed Lecturer and Early Career Researcher in September 2013.