IDENTIFICATION OF MOUSE HISTONE DEACETYLASE-1 AS A GROWTH FACTOR-INDUCIBLE GENE

Reversible acetylation of core histones plays an important role in tra nscriptional regulation, cell cycle progression, and developmental eve nts. The acetylation state of histones is controlled by the activities of acetylating and deacetylating enzymes. By using differential mRNA display, we have identified a mouse histone deacetylase gene, HD1, as an interleukin-2-inducible gene in murine T cells. Sequence alignments revealed that murine HD1 is highly homologous to the yeast RPD3 pleio tropic transcriptional regulator. Indirect immunofluorescence microsco py proved that mouse HD1 is a nuclear protein. When expressed in yeast , murine HD1 was also detected in the nucleus, although it failed to c omplement the rpd3 Delta deletion phenotype. HD1 mRNA expression was l ow in G(0) mouse cells but increased when the cells crossed the G(1)/S boundary after growth stimulation. Immunoprecipitation experiments an d functional in vitro assays showed that HD1 protein is associated wit h histone deacetylase activity. Both HD1 protein levels and total hist one deacetylase activity increased upon interleukin-2 stimulation of r esting B6.1 cells. When coexpressed with a luciferase reporter constru ct, HD1 acted as a negative regulator of the Rous sarcoma virus enhanc er/promoter. HD1 overexpression in stably transfected Swiss 3T3 cells caused a severe delay during the G(2)/M phases of the cell cycle. Our results indicate that balanced histone acetylation/deacetylation is cr ucial for normal cell cycle progression of mammalian cells.