Abstract
The nucleosomal structure of active and inactive c-myc genes has been analyzed in detail in undifferentiated and differentiated cells of the promyelocytic leukemia cell line HL60. The c-myc P2 promoter was never found in nucleosomal configuration, no matter whether c-myc was expressed or not. Differences in the nucleosomal structure, however, were found in the promoter upstream region proximal to a previously described DNase I-hypersensitive site I, at the P0 promoter, and at the P1 promoter and upstream thereof. In these regions nucleosomes were detected in differentiated but not undifferentiated HL60 cells. Similar patterns of nucleosomes as found for active and inactive c-myc genes in HL60 cells were found for active and inactive episomal c-myc genes in stably transfected B cell lines. In these cell lines three activation stages could be described for episomal c-myc constructs: (i) uninducible, (ii) inducible, and (iii) induced. Significant differences in the nucleosomal structure of c-myc were observed for the uninducible and inducible stages, but not for the inducible and induced stages.
Highlights
Activation of the proto-oncogene c-myc is consistently observed in a variety of tumors
In this report we show that changes in the sensitivity to DNase I in c-myc chromatin are accompanied by a remodeling of the nucleosomal structure in the c-myc promoter region
Changes in chromatin structure accompanying downregulation of c-myc in HL60 cells have been studied in detail with DNase I before [27, 28, 48, 50]
Summary
Activation of the proto-oncogene c-myc is consistently observed in a variety of tumors. Factors binding to non-B DNA structures may contribute to c-myc regulation in vivo as well. Scribes a short piece of RNA and pauses ϳ10 to 40 bp downstream to the promoter [30, 31] Activation of these polymerases is suggested to occur by the action of transcriptional activators [32, 33] and to involve phosphorylation of the carboxyl-terminal domain of the large subunit of pol II [34]. The transfected or transgenic c-myc genes consistently turned out to be repressed and not inducible by stimuli that strongly induced the endogenous c-myc This was surprising since most of the constructs displayed a bona fide chromatin structure when compared to the endogenous c-myc. One of the first steps in the activation process of a gene from a repressed state is the rearrangement or disruption of the chromatin structure, which otherwise prevents binding of the basal transcription machinery to the promoter. Access of transcriptional activators and the transcriptional machinery to chromatin-packed DNA is suggested to be enhanced by nucleosome-remodeling complexes such as SWI-SNF and the nucleosome-remodeling factor, NURF [43,44,45,46]
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