Control of cell cycle regulated histone genes during proliferation and differentiation

Proliferation is a requirement during the initial stages of cell and tissue specialization. In most biological systems the down-regulation of proliferation is necessary for initiation of key steps in the differentiation process. We have examined regulatory mechanisms controlling expression of the cell cycle-dependent histone genes, which are functionally coupled with DNA synthesis, in proliferating cells and during the onset of differentiation in several phenotypes including adipocytes. In proliferating cells transcription of the histone genes is up-regulated at the onset of S phase. We have identified a histone H4 proximal promoter element, designated Site II, that mediates cell cycle transcriptional control. The factors interacting with Site II include cdc2, cyclin A, an RB-related protein and interferon regulatory factors (IRFs). Mutational analysis indicates that the distal part of Site II is critical for cell cycle regulation. Equally important for developmental transcriptional control, histone gene expression is repressed when differentiation is initiated. In vivo, we have established loss of Site II occupancy by regulatory proteins; in vitro, factor binding to Site II is not observed post-proliferatively. Deletion analysis indicates that proximal Site II mediates the differentiation response of H4 gene transcription in adipocytes.