Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells

Recent evidence suggests that the Myc and Mad1 proteins are implicated in t he regulation of the gene encoding the human telomerase reverse transcripta se (hTERT), the catalytic subunit of telomerase, We have analyzed the in vi vo interaction between endogenous c-Myc and Mad1 proteins and the hTERT pro moter in HL60 cells with the use of the chromatin immunoprecipitation assay . The E-boxes at the hTERT proximal promoter were occupied in vivo by c-Myc in exponentially proliferating HL60 cells but not in cells induced to diff erentiate by DMSO. In contrast, Mad1 protein was induced and bound to the h TERT promoter in differentiated HL60 cells. Concomitantly, the acetylation of the histones at the promoter was significantly reduced. These data sugge st that the reciprocal E-box occupancy by c-Myc and Mad1 is responsible for activation and repression of the hTERT gene in proliferating and different iated HL60 cells, respectively. Furthermore, the histone deacetylase inhibi tor trichostatin A inhibited deacetylation of histones at the hTERT promote r and attenuated the repression of hTERT transcription during HL60 cell dif ferentiation. In addition, trichostatin A treatment activated hTERT transcr iption in resting human lymphocytes and fibroblasts, Taken together, these results indicate that acetylation/deacetylation of histones is operative in the regulation of hTERT expression.