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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 82; no. 15; pp. 5020 - 5024
• Main Authors: Kaneda, T, Murate, T, Sheffery, M, Brown, K, Rifkind, R A, Marks, P A
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 01.08.1985
• Subjects: Acetamides - antagonists & inhibitors; Animals; Cell Differentiation - drug effects; Cell Division - drug effects; Cell Line; Chromatin - physiology; Chromatin - ultrastructure; Dexamethasone - pharmacology; Gene Expression Regulation - drug effects; Globins - genetics; Leukemia, Erythroblastic, Acute - pathology; Mice; Transcription, Genetic - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.82.15.5020

Previous studies demonstrated that hexamethylenebisacetamide (HMBA)-mediated murine erythroleukemia cell (MELC) commitment to terminal division could be suppressed by dexamethasone. A rapid (less than 2 hr) increase (step-up) in commitment to terminal cell division was observed if, after 60-70 hr 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. In this study, we show that 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 (less than 2 hr) activation (step-up) of alpha 1-globin gene transcription was observed if, after 48-60 hr 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 hr of further culture. Cycloheximide inhibits step-up transcription of both globin genes. Thus, dexamethasone blocks HMBA-mediated modulation of transcription of several nonlinked genes whose expression is altered in a coordinated manner during induced MELC terminal differentiation. Further, the steroid blocks at a late step, a step after that which is rate-limiting to HMBA-mediated MELC differentiation.