A Dynamic Folded Hairpin Conformation Is Associated with alpha-Globin Activation in Erythroid Cells

AM Chiariello and S Bianco and AM Oudelaar and A Esposito and C Annunziatella and L Fiorillo and M Conte and A Corrado and A Prisco and MSC Larke and JM Telenius and R Sciarretta and F Musella and VJ Buckle and DR Higgs and JR Hughes and M Nicodemi, CELL REPORTS, 30, 2125-2135 (2020).

DOI: 10.1016/j.celrep.2020.01.044

We investigate the three-dimensional (3D) conformations of the alpha- globin locus at the single-allele level in murine embryonic stem cells (ESCs) and erythroid cells, combining polymer physics models and high- resolution Capture-C data. Model predictions are validated against independent fluorescence in situ hybridization (FISH) data measuring pairwise distances, and Tri-C data identifying three-way contacts. The architecture is rearranged during the transition from ESCs to erythroid cells, associated with the activation of the globin genes. We find that in ESCs, the spatial organization conforms to a highly intermingled 3D structure involving non-specific contacts, whereas in erythroid cells the alpha-globin genes and their enhancers form a self-contained domain, arranged in a folded hairpin conformation, separated from intermingling flanking regions by a thermodynamic mechanism of micro-phase separation. The flanking regions are rich in convergent CTCF sites, which only marginally participate in the erythroid-specific gene-enhancer contacts, suggesting that beyond the interaction of CTCF sites, multiple molecular mechanisms cooperate to form an interacting domain.

Return to Publications page