Bassem Al-Sady, PhD

Heterochromatin is 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 spreading along the chromosome and precise re-assembly every cell cycle remain obscure, although they critically relate to the potential of heterochromatin to epigenetically regulate genomic loci.

Excitingly, it is now appreciated that heterochromatin spreading plays a key role in the genome partitioning process that shapes cell fate. Heterochromatin exists in small regions, presumably around nucleation sites in embryonic stem cells that expand differentially depending on the lineage track. The same pattern is recapitulated in hematopoiesis, where heterochromatin regions expand as progenitors differentiate. Once the spreading reaction has completed, the new pattern is stably adopted. How heterochromatin spreading from small nucleation sites in stem cells and progenitors is developmentally regulated to drive lineage fates, or how lineages decisions direct differential spreading is completely unknown.

The lab aims to elucidate critical mechanisms that underlie the formation of epigenetic states and their stable inheritance and developmental regulation. To address these mechanisms, we are using two broad approaches, biochemical reconstitution of heterochromatin assembly and single cell analysis of the spreading reaction in yeast and mammalian live cells.

Our local collaborators at UCSF on these questions include the Spitzer, Buchwalter, Ramani, Panning, and McManus labs.