DNA Methylation and Chromatin Structure Regulate PU.1 Expression

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Abstract
Knockout studies have shown that PU.1 is required for the normal development of many blood cell lineages, yet overexpression of this transcription factor in erythroid cells can lead to erythroleukemia. Thus, how the tissue-specific expression of PU.1 is regulated is important to our understanding of hematopoiesis. In this study, we showed that B and macrophage cell lines expressing PU.1 contained DNase I-hypersensitive sites in intron 1 and were hypomethylated at three MspI sites flanking exon 1. Results from studies using several T-cell lines suggested that the pattern of methylation changed as these cells matured. A pre-T cell line that expresses PU.1 contained DNase I-hypersensitive sites in intron 1 and was also hypomethylated at both MspI sites. Other immature T-cell lines had methylated at least one of the Msp I sites and displayed no hypersensitive sites. Mature T-cell lines had a methylation pattern more similar to that of fibroblasts. Treatment of an immature T-cell line with 5-azacytidine resulted in the expression of PU.1 transcripts. These data suggest that the tissue-specific expression of PU.1 is controlled by chromatin structure and DNA methylation and that this may be a mechanism used to shut off PU.1 expression in specific cell lineages during hematopoiesis.