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We investigated the expression characteristics of the fully replication-dependent (FRD) and the partially replication-dependent (PRD) histone gene variants by measuring changes in steady-state mRNA levels during hexamethylene bisacetamide (HMBA)-induced differentiation of murine erythroleukemia (MEL) cells. Between 24 and 60 h after induction, there was a dramatic switch in histone gene expression, such that the ratio of PRD to FRD transcripts increased severalfold over that found in uninduced MEL cells. We demonstrated that this gene switching was not simply a partial or complete uncoupling of PRD gene expression from DNA synthesis. PRD and FRD transcript levels were regulated coordinately upon treatment of uninduced or induced MEL cells with inhibitors of DNA synthesis, protein synthesis, or both. Using several criteria, we were unable to detect any difference in PRD and FRD gene expression under any conditions except in cells undergoing differentiation. MEL cells were arrested at a precommitment stage of differentiation by induction with HMBA in the presence of dexamethasone (DEX). If DEX was subsequently removed, DNA synthesis resumed, the cells underwent commitment, and histone gene switching was observed. In contrast, if both DEX and HMBA were removed, DNA synthesis still resumed, but commitment did not occur and no gene switching was observed. These results imply that histone gene switching is intimately related to the differentiation process.

Histone gene switching in murine erythroleukemia cells is differentiation specific and occurs without loss of cell cycle regulation.