REVERSE TRANSFORMATION AND GENOME EXPOSURE IN THE C6 GLIAL TUMOR-CELLLINE

Reexpression of growth control and differentiation in response to phys iological inducers can be demonstrated in some malignant cell lines, s howing that they are not irreversibly transformed. This switch in phen otype is likely to reflect a changing pattern of gene expression, but it has not been known whether such cellular transitions involve major or only minor modulation of chromatin structure. We have studied growt h control and accessibility of chromatin to DNase I in C6 glioma cells subjected to different growth regimens using an in situ nick translat ion assay to label the most exposed regions of nuclear chromatin. In f ibroblasts and primary glia, exposed chromatin was localized mainly at the nuclear lamina. This readily labeled DNA structure was largely la cking in the malignant C6 glioma. When C6 cells were treated with dibu tyryl cyclic AMP, exposed chromatin was reestablished around the nucle ar periphery. This restoration of a normal genome exposure pattern req uired cytoskeletal integrity. Thus large-scale nuclear reorganization events proceed in parallel with phenotypic normalization. The changes in cell morphology, growth control, cytoskeletal organization, and chr omatin exposure and localization are similar to the reverse transforma tion reaction in CHO-K1 cells, which is also regulated by the cyclic n ucleotide system. Hydrocortisone and dexamethasone also restored genom e exposure in C6 but less markedly than cAMP derivatives. Diverse tran sformed cells can thus respond to growth control stimuli with similar nuclear restructuring events, which presumably underlie changes in gen e expression. Reverse transformation and redifferentiation appear to b e alternative terms describing essentially the same biological phenome non.