DNA methylation during mouse hemopoietic differentiation and radiation-induced leukemia.
OBJECTIVE
To examine DNA methylation in mouse hemopoiesis before and after in vivo exposure to a leukemogenic dose of x-rays, and address whether methylation levels are associated with the relative radiosensitivity of tissues in vivo.


METHODS
The methylation status of control CBA/H and C57BL/6 mouse tissues before and after exposure to 3-Gy x-rays, and myeloid and lymphoid leukemias and lymphomas, was assessed by the direct analysis of the 5-methylcytosine (5-(Me)C) content of DNA, and by Southern blot analysis of genomic repeat sequences.


RESULTS
The DNA 5-(Me)C content of bone marrow is 15% lower than spleen. Together with the analyses of stem (myeloid) and progenitor (lymphoid) leukemias and lymphomas, we found a trend of increasing methylation during hemopoietic differentiation. Exposure to x-rays induced greater cell death in the hypomethylated bone marrow (>80%) than spleen (50%) in vivo, supporting the observed correlation found between methylation status and radiosensitivity of other high-turnover hierarchical tissues. Furthermore, there was an 8% DNA 5-(Me)C content decrease in bone marrow after in vivo exposure to 3-Gy x-rays, but this was genotype dependent, being observed in AML-susceptible (CBA/H) but not AML-resistant (C57BL/6) inbred mice.


CONCLUSIONS
Together these data suggest that methylation status may be related to the relative radiosensitivity of high-turnover hierarchical tissues such as bone marrow and that radiation-induced DNA hypomethylation has a role in radiation leukemogenesis.
Giotopoulos
George
G
Department of Genetics, University of Leicester, Leicester, United Kingdom.
McCormick
Carol
C
Cole
Clare
C
Zanker
Abigail
A
Jawad
Mays
M
Brown
Robert
R
Plumb
Mark
M
D044503:5-Methylcytosine / Q000032:analysis; D000818:Animals; D015139:Blotting, Southern; D001854:Bone Marrow Cells / Q000528:radiation effects; D016923:Cell Death / Q000528:radiation effects; D002454:Cell Differentiation / Q000528:radiation effects; D004247:DNA / Q000737:chemistry / Q000528:radiation effects*; D019175:DNA Methylation / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D007953:Leukemia, Radiation-Induced / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000528:radiation effects; D014965:X-Rays
D044503:5-Methylcytosine; D004247:DNA