"Macrophages are highly specialized cells widely distributed in tissues and active both as immune effectors and as housekeeping phagocytes responsible for maintenance of tissue integrity. Macrophages display a striking heterogeneity that reflects a complex interplay between different micro-environmental signals provided by various tissues (as well as by microbial and endogenous stress signals), and a robust differentiation program that determines macrophage identity.Terminal differentiation depends on the implementation of cell type-specific gene expression programs driven by fate-determining transcription factors (TF). However, the intermediate events linking lineage-specific TFs to the acquisition of the 1- and 3-dimensional genomic organization characteristic of a given cell type (and essential to configure its specific properties and its ability to properly react to the environment) are largely unknown.The objective of this project is to understand how macrophage identity, functional specialization and plasticity are controlled by their specialized genomic organization, which is encoded in mammalian genomes, controlled by specific TFs, and modulated by the microenvironment. By integrating cutting-edge biochemical and genomic techniques, genetics in the mouse, computational approaches and equilibrium thermodynamics, the project aims at describing, and mechanistically deciphering, the specific organization and usage of the genome that is characteristic of macrophages and underlies the acquisition of their functional properties. The output of the project will include concepts and paradigms widely exportable to other cellular systems."