A model is pesented arguing that all transcription enhancers function also as replication enhancers; replication enhancers are thus defined as DNA elements that interact with the core origin to enhance manyfold replication efficiency. This interaction is via proteins bound to the enhancer region with proteins bound to the core ORI and loopig out of DNA. Core ORI by itself functions as a transcriptional enhancer for the gene(s) in the same chromatin loop. One core ORI may require more than one transcription enhancer for its activation. Replication specificity is conferred by a class of replication initiator proteins, comprising cruciform-binding proteins, that need to interact with transcription factors at the core ORI for origin firing; transcription specificity is provided by the interaction of the transcription/replication enhancer with the immediate 5' flanking promoter region. Core ORIs in this model possess a great number of transcription factor binding sites in addition to the initiator protein sites; both initiator proteins and transcription factors cooperate in origin firing. The developmental programs leading to inactivation of specific genes during cell type formation are proposed to be tightly linked with programs leading to the inactivation of ORIs; thus active ORIs are also active enhancers whereas inactive ORIs are linked with transcriptionally-inactive genes and are identical to enhancers inactivated during development or differentiation. Tumor cells are expected to be able to assemble a larger number of active enhancers because of activation of early embryo- or fetal stage-specific transcription factors; this would result in the activation of early developmental stage-specific ORIs.

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