Abstract
We report a multi-omics study in a human cell line with mutations in three subunits of origin-recognition complex (ORC). Although the ORC subunits should bind DNA as part of a common six-subunit ORC, there are thousands of sites in the genome where one subunit binds but not another. DNA-bound ORC2 compacts chromatin and attracts repressive histone marks to focal areas of the genome, but ORC2 also activates chromatin at many sites and protects the genes from repressive marks. These epigenetic changes regulate hundreds of genes, including some epigenetic regulators, adding an indirect mechanism by which ORC2 regulates epigenetics without local binding. DNA-bound ORC2 also prevents the acquisition of CTCF at focal sites in the genome to regulate chromatin loops and indirectly affect epigenetics. Thus, individual ORC subunits may bind to DNA to act as epigenetic and chromosome structure regulators independent of the role of the six-subunit ORC in DNA replication.