![]() Genome-wide identification of mammalian replication origins 1, 2, 3 has been attempted by various methods including trapping of replication-bubbles 4, 5, purification of RNA-primed single DNA strands 6, 7, 8, 9, 10, 11, immunoprecipitation of BrdU-labelled DNA 12 or chromatin immunoprecipitation of origin recognition complex (ORC) 13, followed by microarray hybridization or high-throughput sequencing. This novel panorama of replication reveals how chromatin and transcription modulate the initiation process to create cell-type-specific replication programs. Initiation zones are enriched in origin recognition complex (ORC)-binding sites and better align to origins previously mapped using bubble-trap than λ-exonuclease. Initiation zones are enriched in open chromatin and enhancer marks, even when not flanked by genes, and often border ‘topologically associating domains’ (TADs). Initiation and termination zones are frequently contiguous, sometimes separated by regions of unidirectional replication. Replication fork progression is significantly co-oriented with the transcription. ![]() Replication initiates stochastically, primarily within non-transcribed, broad (up to 150 kb) zones that often abut transcribed genes, and terminates dispersively between them. Here we sequenced highly purified Okazaki fragments from two cell types and, for the first time, quantitated replication fork directionality and delineated initiation and termination zones genome-wide. Existing data have shown strong discrepancies. Despite intense investigation, human replication origins and termini remain elusive.
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