Heterochromatin rewiring and domain disruption-mediated chromatin compaction during erythropoiesis

Mammalian erythropoiesis involves progressive chromatin compaction and subsequent enucleation in terminal differentiation, but the mechanisms underlying the three-dimensional chromatin reorganization remain obscure. Here, we systematically analyze the higher-order chromatin in purified populations of primary human erythroblasts. Our results reveal that heterochromatin regions undergo substantial compression, with H3K9me3 markers relocalizing to the nuclear periphery and forming a significant number of long-range interactions, and that ~58% of the topologically associating domain (TAD) boundaries are disrupted, while certain TADs enriched for markers of the active transcription state and erythroid master regulators, GATA1 and KLF1, are selectively maintained during terminal erythropoiesis. Finally, we demonstrate that GATA1 is involved in safeguarding selected essential chromatin domains during terminal erythropoiesis. Our study therefore delineates the molecular characteristics of a development-driven chromatin compaction process, which reveals transcription competence as a key indicator of the selected domain maintenance to ensure appropriate gene expression during the extreme compaction of chromatin.