Alu distance orders CpG-island promoters from evenly expressed genes to developmental regulators across human hematopoiesis

Abstract Differentiation shifts transcript output among thousands of genes, but how output is partitioned among large gene groups remains unclear. To ask whether promoter architecture marks such groups, we classify 31,962 human genes by promoter CpG island and nearest retroelement. CpG-island genes with a retroelement, mostly an Alu, within 2 kb are expressed more evenly across tissues than those with more distant ones at matched island length. By distance to the nearest Alu, CpG-island promoters form an axis from Alu-near (within 2 kb) through Alu-mid to Alu-far promoters (none within 4–8 kb), with longer islands and less even expression. In blood progenitors and lymphocytes, Alu-near promoters carry more H3K4me3 and Alu-far promoters more H3K27me3. The methylation boundary lies about 1 kb from the transcription start site at Alu-near promoters, nearer in less expressed genes, and farther at Alu-mid and Alu-far promoters. In a bone-marrow hierarchy, the share of Alu-near genes flanked by Alu on both sides, about one third of output, is larger in progenitors than in hematopoietic stem cells and follows proliferation, whereas the Alu-far share, below 1%, is larger in stem cells, an excess led by MEIS1 and HOX regulators. Pre-specified tests support both directions in an independent bulk dataset and each in one of two single-cell datasets. Alu distance thus defines promoter classes whose shares differ in opposite directions between these cells, a difference hidden in the total CpG-island share.