Very little is known about the global organization and regulation of the replication program. Recent advances in genomic methods allow the genome-wide description of the time of replication in mammals. Nevertheless, the spatial information about replication initiations (origin of replication) is still sparse. Such information is crucial for studying mechanistic aspects of replication regulation since the time of replication is determined mainly by the time each origin is activated. In Originome I propose to develop novel genome-wide approaches that will allow origin mapping both in the cell population and the single cell levels. Applying these methods to multiple tissues, growth conditions and organisms, will put me in an excellent position for studying the regulation of the replication machinery. I am planning to combine bioinformatics, comparative genomics and reverse genetics tools to decipher the cis-acting elements that participate in the regulation of the replication program. Successful mapping of origins and characterization of their mode of regulation have broad implications not only in the field of DNA replication. First, replication stress is one of the initial causes of cancer. Therefore, I am planning to decipher the changes in the replication program that occur in response to stress in order to better understand the transformation process. Second, better understanding of replication regulation will allow studying systematically the association between time of replication, transcription and chromatin structure. Taken together, by moving the field of DNA replication from a descriptive into a mechanistic stage, Originome will set the stage for a variety of experimental approaches for deciphering replication organization and its effects on transcription, chromatin structure and cancer transformation.