Co-workers:

We study how DNA methylation and silencing histone modifications contribute to regulation of gene expression in mammalian cells. In particular, we investigate the molecular mechanisms that guide the establishment of DNA methylation patterns in embryogenesis and lineage commitment, as well as during cellular transformation into cancer. We also study the crosstalk between DNA methylation and histone modifications during the establishment and propagation of silenced chromatin states.
In early mouse development, lineage-specific DNA methylation patterns are established de novo in the post-implantation blastocyst by DNA methyltransferase enzymes Dnmt3a and Dnmt3b. However, evidence exist that there are additional proteins, which facilitate the action of Dnmt enzymes either globally or in a locus-specific manner. We recently found that, in the absence of putative chromatin remodelling ATPase Lsh/ Hells and G9a/GLP complex of histone H3K9 methylases DNA methylation patterns at specific loci cannot be appropriately established in embryonic lineage cells. Detailed investigation of Lsh-/- mouse embryonic fibroblasts indicated that Lsh is essential for local accumulation of de novo DNA methyltransferases and G9a/GLP complex most likely by generating hypoacetylated chromatin via its direct association with Dnmt3b and histone deacetylase enzymes Hdac1 and Hdac2 (Figure 1). To address further the dynamics of DNA methylation establishment in early development and the molecular function of Lsh in this process, we are generating ES cells and mice with conditional Lsh alleles.
The conversion of normal cells into cancer typically involves several steps resulting in the acquisition of unlimited growth potential (immortality). Both genetic and epigenetic changes have been detected in a number of different cancer cell types. Generally, these changes lead to the activation of oncogenes and the inactivation of tumour suppressor and pro-apoptotic genes. Although a number of tumour suppressor genes have been shown to be silenced by promoter DNA methylation, it is yet unclear whether epigenetic changes contribute directly to cancer and if so when, where and how do they cooperate with genetic changes during the transformation process. In order to address these questions and study the global epigenetic changes associated with cellular immortalisation and transformation, we have generated a human cancer cell model with defined genetic background. Following the epigenetic changes in these cells has led to interesting and unexpected findings.

Selected publications:

 
Myant, K. and Stancheva, I. (2008) LSH cooperates with DNA methyltransferases to repress transcription., Mol Cell Biol, 28, 215-226.
Myant, K., Termanis, A., Sundaram, A. Y., Boe, T., Li, C., Merusi, C., Burrage, J., de Las Heras, J. I., and Stancheva, I. (2011). LSH and G9a/GLP complex are required for developmentally programmed DNA methylation. Genome Res 21, 83-94.
Stancheva, I. (2011) Revisiting heterochromatin in embryonic stem cells, PLoS Genetics 7(6), e1002093.

Research in Stancheva lab is funded by: