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Changes of DNA methylation and chromatin structure in the human
myeloperoxidase gene during myeloid differentiation
M Lubbert, CW Miller and HP Koeffler
Cedars Sinai Medical Center, UCLA Department of Medicine.
Expression of the myeloperoxidase (MPO) gene is tightly regulated in a
tissue- and development-specific manner. Accumulation of MPO messenger RNA
(mRNA) occurs only at the late myeloblastic and promyelocytic stages of
myeloid differentiation and is negligible at other stages of myeloid
development and in other tissues. The goal of our studies was to begin to
understand the events that occur to control MPO gene expression during
normal granulocytopoiesis. Chromatin structure of the MPO gene was
evaluated by DNase I treatment of isolated nuclei and Southern blot
analysis. No detectable DNase I hypersensitive sites were found in the
region of the MPO gene in non-myeloid cells. One site was present in the 5'
upstream region in myeloid cells that are developmentally too immature to
transcribe MPO. Three sites of hypersensitivity in the regions of the
putative MPO promoter and upstream region occurred in MPO-expressing
promyelocytes. These sites were markedly reduced in terminally
differentiated, non-expressing myeloid cells. Analysis of DNA methylation
of the MPO gene using methylation-sensitive restriction enzymes showed that
the gene was highly methylated in non-myeloid cells. Stepwise demethylation
occurred in myeloid cells developmentally too immature to transcribe MPO.
Maximal demethylation in the 5' gene region occurred in MPO-expressing
promyelocytes. This methylation pattern did not change in terminally
differentiated, MPO non-expressing myeloid cells. A somatic hybrid cell
formed by fusion of HL-60 (MPO-expressing cells) and PUT (MPO non-
expressing lymphoid cells) extinguished expression of MPO and showed a
chimeric pattern of MPO gene methylation, suggesting that demethylation is
necessary but not sufficient for expression of the MPO gene. Our studies
show that demethylation and DNase I hypersensitivity of the MPO gene were
associated with a tissue-dependent potential for MPO gene expression that
preceded the developmental ability to express MPO mRNA.
Volume 78,
Issue 2,
pp. 345-356,
07/15/1991
Copyright © 1991 by The American Society of Hematology
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