Global chromatin organization is highly conserved across cell types and species. Indeed, most somatic cells accumulate compact heterochromatin at the nuclear periphery while the less condensed euchromatin is internally localized in the nucleus. This organization highly depends on the association of heterochromatin with the nuclear lamina, which in turn participates in gene repression. Changes in association of specific genomic loci with the nuclear lamina are correlated with differentiation, suggesting a role for nuclear lamina association in the establishment of cell identity. In rupture with the classical view that the nuclear lamina stands as the main determinant of heterochromatin accumulation at the nuclear periphery, I propose that it rather results from an equilibrium between attraction at the nuclear lamina and repulsion from the adjacent nuclear compartment: the nuclear pores. I hypothesize that changes in nuclear pore density may therefore be an important mechanism allowing regulation of this equilibrium during cellular transitions. I will use oncogene-induced senescence in human fibroblasts and differentiation of mouse embryonic stem cells as two models of cellular transitions associated with changes in nuclear pore density to ask (1) how heterochromatin is repelled from nuclear pores, (2) how nuclear pore-dependent global heterochromatin reorganization affects gene activation in senescence and (3) how nuclear pores affect association of specific genomic loci with the nuclear lamina during differentiation. I will use synthetic biology approaches to modify the position of nuclear pore components or genomic loci and interrogate the relationship between nuclear positioning and genome regulation at the single cell level using mainly microscopy analysis. aNChOr will provide a mechanistic analysis of global scale chromatin organization by nuclear pores and how changes in the equilibrium between the nuclear lamina and the nuclear pores can affect cellular fate.