H3K37me1 couples transcription with DNA replication origin selection

DNA replication initiation in higher eukaryotes occurs at thousands of sites distributed throughout the genome and follows a defined temporal program. However, replication origins are not determined by a conserved DNA motif, and how specific genomic regions are selected for initiation remains poorly understood. Here, we identify a transcription-associated histone modification in human cells, mono-methylation of histone H3 lysine 37 (H3K37me1), and show that it regulates the spatial organization of replication initiation. H3K37me1 is enriched across actively transcribed gene bodies, and its depletion leads to a redistribution of replication origin activity toward intragenic regions. We show that H3K37me1 limits the association of the MCM2–7 replicative helicase with transcribed chromatin, thereby restricting intragenic origin usage. Consistently, loss of H3K37me1 increases both MCM2–7 occupancy and replication initiation across gene bodies. Collectively, our findings uncover a chromatin-based mechanism that couples transcription with DNA replication origin selection by limiting unscheduled origin firing within transcribed regions.