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Our Research

 
One of the most fundamental questions in biology is how during development and differentiation the pluripotent embryonic cells carrying identical genomes acquire very different cell fates and establish specialized gene expression programmes that are stable for many cell generations. In this process, expressing the right genes at the right time is as important as silencing those that are not needed. While gene activation is driven by gradients of signalling molecules and transcription factors, gene silencing is supported by DNA methylation and chromatin modifications carried out by specialized enzymatic activities. Mutations in many components of the epigenetic gene silencing machinery lead to variety of human disorders, including cancer.
 
Our laboratory studies how DNA methylation contributes to regulation of gene expression in mammalian cells. In particular, we investigate the molecular mechanisms involved in the establishment of DNA methylation patterns during mammalian development and cellular transformation. We are also interested in how DNA methylation patterns are stably maintained in order to facilitate heritable propagation of specialized gene expression programmes. Finally, we aim to unravel the crosstalk between chromatin structure, modifications and DNA methylation.

 

 

Regulators of DNA methylation

 
DNA methylation is highly dynamic in germ cells and during the early development of mammalian embryos. In primordial germ cells (PGCs) DNA methylation is erazed and new parent-of-origin patterns are established in mature gametes genome-wide and at differentially methylated regions of imprinted genes. After fertilization, DNA methylation is reprogrammed again in the developing embryo. At blastocyst stage the overall levels of 5-methyl cytosine are low and most gene promoters are not methylated. New patterns of DNA methylation are established in embryonic lineage cells by the epiblast stage E6.5 and these continue to change in differentiated tissues. Although DNA methyltransferases are absolutely essential for this process, there are other proteins that regulate the action of these enzymes either globally or at specific genomic loci. We use a variety of tools to study the regulators of DNA methylation such as chromatin remodeling ATPase LSH and histone methyltransferases G9a and GLP.  You can read more about this research here 

 

                                

               

 

DNA methylation and cancer

 
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 include activation of oncogenes and inactivation of tumour suppressor and pro-apoptotic genes. Although a number of tumour suppressor genes can be silenced by promoter DNA methylation, it is yet unclear whether epigenetic changes contribute directly to cancer initiation and progression 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 landscape 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. Read about this research here.