27 May DNA sequences in chronic lymphocytic leukaemia (CLL).
The human genome is the recipe book for making every protein that cells need to function. There are more than 20,000 genes encoding for proteins, and yet only 30% of our total DNA sequence fall within these genes. Most of our genome is comprised of highly repetitive sequences of DNA with diverse functions. In our study, we examined one such group of repetitive DNA sequences, called ‘retrotransposons’, in chronic lymphocytic leukaemia (CLL). Retrotransposons have the ability to copy & paste themselves throughout the genome to create new versions of themselves, but this process is detrimental for cells as it leads to genomic instability and so it is normally suppressed through an epigenetic mechanism called DNA methylation. DNA can be chemically modified (methylated) where a C is followed by a G in the sequence, which turns off gene expression and silences retrotransposons. In cancers and leukaemias, the normal regulation of DNA methylation is lost, resulting in expression of previously-silenced oncogenes, and the silencing of genes that suppress tumour growth. Our work examined loss of DNA methylation at retrotransposons in CLL and how this impacts upon the expression of nearby genes. We identified specific retrotransposons in the genome that lose their methylation very early in the development of the disease, even being detectable in some individuals years before their diagnosis. Through funding from Bright Red, we have been able to demonstrate that the cause of this loss of methylation can be genetic. By sequencing DNA samples, we showed that loss of methylation is associated with C-to-T mutations that prevent these regions from being methylated. This can potentially lead to oncogenes being switched on and promoting progression of the disease. We are now planning to investigate how these mutations originate – are they associated with ageing or environmental factors?
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