UCSF

Cell type specification in multicellular systems is due, at least in part, to differential access to and usage of the genomic DNA which is common to all cells, leading to cell type specific gene expression. This genomic pattern in enacted through the formation of gene-repressive heterochromatin, a nuclear ultrastructure, which silences transcription of genes embedded in the underlying DNA that are orthogonal to the intended cell fate and expands progressively, in a process known as spreading, while cells proceed through lineage commitment. Importantly, once the cell type specific pattern of gene expression has been established, it must be recapitulated over repeated cell division to ensure faithful maintenance of cell identity and avoid disease. Both the mechanisms which direct this process of differential expansion and the features of heterochromatin domains which are critical to its robust inheritance have not been fully elucidated. Utilizing a genetically tractable fission yeast model that recapitulates features of the metazoan chromatin environment, we interrogated the requirements for spatial and temporal regulation of heterochromatin domain formation. We find that at cell identity loci, robust gene silencing and the capacity to remember heterochromatin states over repeated division requires the collaboration of multiple sequence elements with distinct spreading properties and capacities to resist chromatin perturbations. Additionally, we find chromatin context dependent requirements for genetic regulation of the spreading process. Lastly, we described a mechanism for regulating the spatial expansion of heterochromatin domains that relies on the mutually antagonistic signals and properties that differ between hetero- and eu- chromatin domains.