The development of complex organisms entails sequence-specific transcription factors and also epigenetic marks such as DNA methylation. Methylation of DNA occurs on cytosines and can be transmitted over many cell generations to sustain epigenetic memory. Yet we still know very little about how DNA methylation is attracted to specific sites in the genome and how this ultimately influences cellular destiny. This is a fascinating challenge that deserves intensive investigations because DNA methylation is critical for both normal and pathological cellular functions.I propose to initiate an ambitious research project that will identify novel functions and regulators of DNA methylation in the mouse. My objectives are to (1) use genome-wide mapping and elegant mouse genetics to elucidate the role of DNA methylation in lineage identity in physiological contexts in vivo; (2) design original high-throughput RNAi screens to identify novel factors that shape the DNA methylome in mammalian genomes; and (3) develop tools for targeted engineering of the methylome that will allow, for the first time, to test predictive models by interfering with DNA methylation at specific sites in the genome.This combination of innovative approaches will lead to major breakthroughs that go beyond the current state-of-art. We will assess causal and mechanistic relationships between DNA methylation and cell identity at the genome level, and identify novel epigenetic regulators for long term studies to characterize their mechanism of action. This will improve our understanding of the epigenetic mechanisms of genome regulation and potentially lead to novel therapeutic applications for cell reprogramming or disease treatment. The ERC grant will give me the necessary financial resources to recruit talented people and initiate this ambitious research program, and therefore will significantly contribute to consolidate my leadership in the field.