Molecular analysis of erythropoiesis: A current appraisal

Abstract

This article considers recent evidence concerning the molecular mechanisms involved in the coordinate regulation of gene expression during red blood cell (RBC) differentiation. Contrary to popular belief, recent evidence shows that only a few of the characteristic RBC proteins are restricted to the erythroid lineage: apart from the globins, an RBC lipoxygenase and (possibly) glycophorin are the only examples for which there is reasonably good evidence. In contrast, the proteins forming the RBC cytoskeleton (spectrin, ankyrin, band 4.1, actin and possibly the major anion exchange transmembrane protein by which the cytoskeleton is attached to the plasma membrane) have closely-related variants in other cell types. Yet two beta-spectrin variants are found exclusively in certain terminally differentiated cells, often only in certain specific regions of the cell membrane. Certain RBC isozymes (e.g. for pyruvate kinase and carbonic anhydrase) and an RBC 19 kD protein (ep19) are also expressed only in a subset of other cell types. This illustrates the importance of gene families which are differentially regulated in certain subsets of cell types during differentiation and development. The expression of the globin genes seems to be regulated mainly at the transcriptional level, although transport of these transcripts to the cytoplasm may be controlled by interactions with other RNAs: stabilisation of globin mRNAs by ribonucleoprotein complexes in the cytoplasm may also be important. In fact, the expression of the globin genes involves two distinct phases: first, structural changes occur in the chromatin surrounding the genes (as determined by sensitivity to digestion by nucleases) and these can be maintained independently of any subsequent transcription. In many cases, these nuclease-sensitive sites in the chromatin correspond to low-level transcription initiation sites and to DNA sequences with regulatory functions when the isolated genes are assayed for transcription in vivo after transfection into cells. How the unlinked alpha- and beta-globin genes are coordinately regulated is not yet understood. Indeed, the alpha- and beta-gene promoters have quite different properties as judged by their responses to DNA replication and to factors known to affect viral gene function (e.g. the cis-acting SV40 enhancer elements and the trans-acting adenovirus regulatory protein, Ela). Other evidence shows that a nuclear protein present only in erythroid cells is able to bind to the beta-globin gene precisely in the region that is hypersensitive to nuclease digestion in chromatin from erythroid cells.(ABSTRACT TRUNCATED AT 400 WORDS)