Co-ordinating the patterns of gene expression that drive the development of a complex organism requires multiple layers of regulation, extending from sequence-based DNA-protein interactions to higher-order architecture of the genome.The spatial organization of chromatin within the nucleus is thought to reflect a functional compartmentalization that mirrors changes in cell fate. Recently, the signals and proteins involved in the topological organization of heterochromatin in complex organisms started to be addressed. In C. elegans, cell differentiation is accompanied by a cell-type specific 3D re-organization of the nucleus, leading to the internal localization of active tissue-specific promoters and the perinuclear sequestration of repressed tissue-specific promoters.Through a highly successful genome-wide RNAi screen the Gasser laboratory identified histone H3K9 methylation as an essential signal for the peripheral anchoring of heterochromatin in undifferentiated embryonic C. elegans cells. However, as embryos differentiate into worms the perinuclear sequestration of heterochromatic arrays is re-established, even in absence of H3K9 methylation. This strongly argues that alternative, unknown anchoring pathways that are induced during differentiation exist and orchestrate heterochromatin spatial segregation.With this project, I aim to identify the chromatin signals and “reader” molecules triggering heterochromatin anchoring at the nuclear periphery in differentiating worm cells. Moreover, I will determine whether compartmentalization of chromatin is required for appropriate cell-type differentiation. I predict that defects in tissue maintenance will arise, albeit possibly subtle ones, when chromatin fails to segregate into active and inactive domains.Overall, this project will significantly contribute to understanding how genomic nuclear organization impinges on epigenetic regulation.