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In multicellular organisms, each cell contains the same genome, yet, cell of distinct identities can emerge that contain genetically stable gene expression states. This is possible in part due to nuclear ultrastructures that maintain unwanted cellular and developmental programs in a heritable “off” state.
One such ultrastructure is heterochromatin, a specialized protein-nucleic acid composite that silences the activity of genes over large contiguous chromosomal regions, and that has been visualized as a distinct nuclear ultra-structure for almost a century. Remarkably, the mechanisms guiding heterochromatin self-assembly and propagation remain obscure, although they critically relate to the potential of heterochromatin to epigenetically regulate genomic loci.
Assembly of heterochromatic structures occurs at least partially by a template guided polymerization-like process known as “spreading”. When heterochromatin spreads over a given gene in the same way every cell cycle, gene silencing is propagated epigenetically. Conversely, imprecise or illegitimately initiated spread can cause a gene to become de-repressed, repressed de novo, or behave in a variegated manner. This variability, in turn, connects heterochromatin assembly to numerous diseases including certain leukemias, breast and skin cancers, where heterochromatic silencing becomes aberrant at key loci.
The lab is interested to elucidate two critical mechanisms that underlie normal inheritance of epigenetic states and failure of this process in disease:
1) What is the biochemical basis of sequence-indifferent spreading of heterochromatic information along the chromosome?
To address this question, we are biochemically reconstituting the spread of heterochromatin signaling histone marks along synthetic chromatin substrates.
2) What is the nature of the cellular regulatory architecture that ensures the fidelity of this process through the cell cycle?
To unravel this architecture, we are taking a single cell genetic approach in the yeast Schizosaccharomyces pombe. In particular, we have devised a unique Heterochromatin Spread Sensor that will form the platform to dissect the requirements for heterochromatin spreading, and regulation of the epigenetic fidelity of this process.