Modulation of gene expression during terminal cell differentiation.

Inducer-mediated differentiation of MELC provides a model to define the cellular and molecular mechanisms involved in terminal cell differentiation (Fig. 2). (Formula: see text) Fig. 2. HMBA-mediated cellular and molecular changes during induced MELC terminal erythroid differentiation. See text for detailed discussion. HMBA-induced differentiation is accompanied by an acceleration of transcription at the alpha 1 and beta maj globin loci. MELC are virus-transformed cells blocked in erythroid lineage development. MELC have acquired a pattern of DNA hypomethylation, nuclease sensitivity, and partially disrupted nucleosome configuration of the chromatin containing the transcriptionally inactive alpha 1 and beta maj globin domains, which distinguish them from the domains of nonerythroid transcribed genes, e.g. immunoglobulin or albumin, or ribosomal RNA genes which are actively transcribed in uninduced cells. HMBA-mediated MELC differentiation is associated with changes in chromatin configuration, characterized by an increased disruption of the nucleosome structure across the structural nucleotide sequences of alpha 1 and beta maj globin genes and the appearance of nuclease hypersensitive sites 5' upstream from the alpha 1 and beta maj genes. The alteration in chromatin structure appears to precede increased transcription of these genes. Inducer-mediated loss of proliferative capacity involves a complex multistep process during which the cells accumulate factor(s), probably mRNA(s), required for the synthesis of proteins which are, in turn, required for expression of the commitment process and activation of globin gene transcription. Characterization of these genes whose expression is modulated in HMBA-induced commitment to terminal cell division is in process.