Group Leader: Dr Steen Ooi
The central dogma of biology is that genes code for proteins, which in turn are responsible for building cells and bodies. Our bodies are composed of diverse cell types, all specialized for specific tasks, which ensure our normal development and survival. This requires the correct expression of all genes present in our genome. One way in which this is controlled is through modifications to our genetic material that, while leaving the underlying sequence information unchanged, affects how it is packaged. Errors in where these modifications occur throughout the genome play an important contributing role in the development of diseases such as cancer. Our group uses genetic, cell and molecular biological approaches to understand how these modifications are controlled and correctly interact.
Within the field of mammalian gene regulation, it is widely accepted that as well as sequence specific transcription factors, modifications to DNA (such as methylation of cytosine residues) and chromatin (through the incorporation of histone variants and post-translation modifications) contribute to gene silencing and activation. These mechanisms/processes underlie epigenetic phenomena, which refer to the transmission of deviations in cellular function and behavior that cannot be explained by genetic differences. Alterations in epigenetic processes are a key contributory aspect of complex, non-infectious diseases such as cancer and understanding how they are regulated will help in the development of more targeted, and therefore effective, therapies.
Our lab is interested in deciphering how global patterns of DNA methylation, the best-characterized epigenetic modification, are correctly regulated. Although much is known about the enzymes (DNMTs) that mediate this modification, the signals responsible for their recruitment to the correct target loci where DNA methylation normally occurs, remain poorly defined. Using a combination of mouse genetics, tissue culture and molecular biology, we aim to test the hypothesis that the chromatin scaffold itself is an integral feature necessary for targeting DNMTs. We also aim to understand which chromatin-affecting processes are important and their involvement in disease processes.
- Nancy Stathopoulou (Postdoctoral Research Associate)
- Gehad Youssef (Postdoctoral Research Associate)
- Jyoti Bikram Chhetri (Research Technician)
G.Vlachogiannis, Niederhuth, C.E.,Tuna S., Stathopoulou, A., Viiri, K., de Rooij, D.G., Jenner, R.G., Schmitz R.J., Ooi, S.K.T. “The Dnmt3L ADD controls cytosine methylation establishment during spermatogenesis”. Cell Reports 2015, 10, 944-956
Stathopoulou, A, Lucchiari, G., Ooi, S.K.T., “DNA methylation is dispensable for suppression of the Agouti viable yellow controlling element in murine embryonic stem cells”. PLOS ONE, 2014. 9, e107355
Kao, T.H., Liao, H.F., Wolf, D., Tai, K.Y., Chuang, C.Y., Lee, H.S., Kua, H.C., Hata, K., Zhang, X., Cheng, X., Goff, S.P., Ooi, S.K.T., Bestor, T.H., Lin, S.P. Ectopic DNMT3L triggers assembly of a repressive complex for retroviral silencing in somatic cells. J.Virol., 2014, doi:10.1128/JVI.01176-14
Stadtfeld, M., Apostolou, E., Ferrari, F., Choi, J., Walsh, R.M., Chen, T., Ooi, S.K.T., Kim, S.Y., Bestor, T.H., Shioda, T., et al. (2012). Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all-iPS cell mice from terminally differentiated B cells. Nature Genetics, 2012, 44, 831.
Ooi S.K.T., Wolf D, Hartung O, Agarwal S, Daley GQ, Goff SP and Bestor TH. Dynamic instability of genomic methylation patterns in pluripotent stem cells. Epigenetics and Chromatin, 2010, 3, 17
Ooi S.K.T., O’Donnell AH and Bestor TH. Mammalian cytosine methylation at a glance. J. Cell Science, 2009, 122, 2787 PubMed
Ooi S.K.T., Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin S, Allis CD, Cheng X and Bestor TH. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature, 2007, 448, 714. PubMed