biostudies-literatureHardison RCNIDDK NIH HHS341-367https://www.ebi.ac.uk/biostudies/studies/S-EPMC12452803biostudies-literatureUnknown59(1)Studies of globin gene clusters have established many paradigms of gene regulation. This review focuses on the α- and β-globin gene clusters of humans and mice, summarizing important insights from high-throughput biochemical assays and directed genetic dissections and emphasizing similarities across the types of gene clusters and between species. The overall arrangements and architectures are similar, with each gene cluster being localized within a topologically constrained unit of chromatin containing a multicomponent enhancer (i.e., a locus control region) and other regulatory elements bound by a similar set of transcription factors and coactivators. Differential expression of the globin genes within each cluster during ontogeny is associated with changes in contacts with the locus control region and involves the action of gene-specific repressors. Detailed study of the fetal β-like <i>HBG1</i> and <i>HBG2</i> globin genes has revealed a remarkable diversity of regulatory pathways that provide candidates for therapeutic approaches to reactivate these genes for β-hemoglobinopathies.Annual review of geneticsMechanisms of Globin Gene Regulation in Mammals.PMC12452803R01 DK054937R24 DK106766Hardison RCfalseMechanisms of Globin Gene Regulation in Mammals.Studies of globin gene clusters have established many paradigms of gene regulation. This review focuses on the α- and β-globin gene clusters of humans and mice, summarizing important insights from high-throughput biochemical assays and directed genetic dissections and emphasizing similarities across the types of gene clusters and between species. The overall arrangements and architectures are similar, with each gene cluster being localized within a topologically constrained unit of chromatin containing a multicomponent enhancer (i.e., a locus control region) and other regulatory elements bound by a similar set of transcription factors and coactivators. Differential expression of the globin genes within each cluster during ontogeny is associated with changes in contacts with the locus control region and involves the action of gene-specific repressors. Detailed study of the fetal β-like <i>HBG1</i> and <i>HBG2</i> globin genes has revealed a remarkable diversity of regulatory pathways that provide candidates for therapeutic approaches to reactivate these genes for β-hemoglobinopathies.2025-01-01T00:00:00Z2025 Nov2026-05-31T03:15:51.033Z2026-05-31T03:07:44.549ZS-EPMC124528034082978110.1146/annurev-genet-020325-095743