Regulation of Gene Expression during the Cell Cycle and during the Proliferation/Differentiation Transition

Our laboratory is investigating the control of cell proliferation and its relationship to the onset and progression of differentiation. Our experimental approach is to examine molecular mechanisms involved in regulating specific genes that are expressed in actively proliferating cells, changes in the expression of these genes during the down-regulation of cell growth, and the initiation of expression of cell and tissue specific genes as cells differentiate.

One area of emphasis is the regulation of human histone gene expression. Histones are expressed primarily during the S phase of the cell cycle and are intimately involved with genome replication. We have focused on transcriptional regulation of the H4, H3 and H1 histone genes. In the H4 and H3 genes two sites of in vivo protein-DNA interaction have been identified in the proximal promoter region. Site I sequences influence the level of transcription while Site II sequences contain the cell cycle regulatory element and are also important for on/off regulation of this gene. We are continuing our characterization of the complex array of transcription factors and cell cycle regulatory proteins that bind these regulatory sequences to modulate expression both during the cell cycle and in the transition between proliferation and differentiation.

A second area of interest is the osteocalcin gene, which is normally expressed only in post-proliferative cells, primarily those of bone. We are investigating the many-faceted regulation of this gene both in terms of tissue-specificity and with regard to its activation as cells cease proliferating and assume a mature bone cell phenotype. The changes in chromatin structure and nuclear matrix association of the histone and osteocalcin genes that accompany changes in gene expression are being defined.