Cell cycle dependent role of HDAC1 for proliferation control through modulating ribosomal DNA transcription.

Ribosome biogenesis and ribosomal DNA transcription are closely correlated with the growth and proliferation of cells, with these processes being under tight epigenetic control. We have investigated the effect of ectopically expressed murine HDAC1 in reporter assays, on ribosomal DNA transcription, cell cycle progression and proliferation in transfected mammalian cells. Ectopically expressed mHDAC1 represses transcription in ribosomal reporter assays driven by ribosomal promoter elements in NIH3T3 cells as well as Cos-7 cells. Following stable transfection of NIH3T3 cells, flag-tagged HDAC1 is assembled into functional, enzymatically active HDAC-complexes that display correct nuclear localization. Induction of flag-HDAC1 expression in NIH3T3 cells caused a cell-cycle phase specific reduction in the initiation of endogenous rDNA transcription, reflected in a reduction of nascent rRNA as well as a marked depression of proliferation due to prolongation of G2-phase. This was substantiated by FACS analysis and cyclin B1 expression analysis. However, prolongation of the G2-phase in HDAC1-overexpressing cells finally led to overcompensation and thus to an increase in total ribosomal RNA. The transient downregulation of rRNA synthesis after induction of HDAC1 overexpression led to a prolongation of G2-phase. These observations were most likely a consequence of HDAC1-mediated deacetylation of upstream binding factor (UBF).