Regulation of epigenetics and chromosome structure by human ORC2 [CUT&RUN]

The six subunit Origin Recognition Complex (ORC) is a DNA replication initiator that also promotes heterochromatinization in some species. A multi-omics study in a human cell line with mutations in three subunits of ORC, reveals that the subunits bind to DNA independent of each other rather than as part of a common six-subunit ORC. While DNA-bound ORC2 was seen to compact chromatin and attract repressive histone marks, the activation of chromatin and protection from repressive marks was seen at a large number of sites. The 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. Thus, individual ORC subunits are major regulators, in both directions, of epigenetics, gene expression and chromosome structure, independent of the role of ORC in replication.