Gene expression during terminal differentiation: dexamethasone suppression of inducer-mediated alpha 1- and beta maj-globin gene expression.

Abstract

Hexamethylenebisacetamide (HMBA)-mediated murine erythroleukemia cell (MELC) commitment to terminal division could be suppressed by dexamethasone. A rapid (< 2 h) increase (step-up) in commitment to terminal cell division was observed if, after 60-70 h in culture with inducer and steroid, MELC were transferred to medium with HMBA alone. This step-up commitment was not inhibited by actinomycin or cordycepin but was blocked by cycloheximide. Dexamethasone blocks HMBA-mediated activation of .alpha.1- and .beta.maj-globin gene transcription but not the induced chromatin change characterized by appearance of DNase I-hypersensitive regions upstream from the 5'' cap sites of the .alpha.1- and .beta.maj-globin genes. A rapid (< 2 h) activation (step-up) of .alpha.1-globin gene transcription was observed if, after 48-60 h in culture with HMBA and dexamethasone, MELC were transferred to medium with HMBA alone. Activation of transcription of the .beta.maj-globin gene requires 12-24 h of further culture. Cycloheximide inhibits step-up transcription of both globin genes. Dexamethasone blocks HMBA-mediated modulation of transcription of several nonlinked genes whose expression is altered in a coordinated manner during induced MELC terminal differentiation. The steroid blocks at a late step, a step after that which is rate-limiting to HMBA-mediated MELC differentiation.