The Epigenetic Control of Gene Expression in Leukaemia and Haematopoiesis

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There are many specialized cells in our body designed to carry out different specific tasks, and yet they all contain the same genetic information. During development, cells receive information that they translate into specific developmental outputs, usually without altering their DNA sequence. Changes in cell phenotype that do not alter the DNA sequence are referred to as “epigenetic”. Human diseases such as cancer often result from changes in gene expression patterns that are not always associated with DNA mutations, thus epigenetic changes are also a key mechanism in human disease. In living cells, genes do not exist as “naked” DNA, but as a highly conserved protein/DNA complex termed chromatin. The basic subunit of chromatin is the nucleosome, which consists of DNA wrapped around an octamer core of globular histone proteins, two each of H2A, H2B, H3, and H4.The N terminal "tails" of these histone proteins are chemically modified with "marks" such as methylation or acetylation. The specific carriers of epigenetic information have not been completely worked out, but emerging work over the past decade has suggested that epigenetic information is established in part by the modification of histone tails. We are specifically interested in how changes in histone methylation lead to transcriptional misregulation in human disease. As a system for asking specific questions about this very complex problem, I work on the Mixed Lineage Leukemia 1 (MLL1) protein, a histone methyltransferase that controls gene activation during development. Mutations in MLL1 also cause aggressive leukaemias in both children and adults. Specific information about MLL1 activity will not only provide potential therapeutic information for this subset of human leukemias, but will also have broader implications for stem cell development and the epigenetic regulation of gene expression in other human diseases.