ASF1B promotes erythropoiesis by regulating the establishment and dynamics of H3.3 nucleosomes

Abstract ASF1B, a histone chaperon, was synergistically expressed together with the H3f3a gene encoding the histone variant H3.3 during erythropoiesis. However, the mechanism underlying this coordination is still unclear. We found that ASF1B is a key regulator of erythrocyte development by influencing embryonic/fetal globin and H3f3a gene in erythroid progenitor cells. Moreover, the regulation of H3f3a by ASF1B was predominant over its family member ASF1A and H3.3-specific chaperone HIRA. ASF1B occupied more than 70% of H3.3 nucleosomes at erythroid gene promoters and enhancers. ASF1B suppressed the expression of embryonic/fetal globin genes in normal and disease condition by altering H3.3 enrichment and chromatin accessibility. Strikingly, the regulatory pathway of ASF1B in H3.3 deposition involved the recruitment of chromatin remodeler BRG1 and accumulation of H3K27ac in active chromatin. In summary, ASF1B plays a crucial role in H3.3 enrichment and globin gene expression that highlights the therapeutic potential of ASF1B in targeting β-globin hemoglobinopathies.