SATB1ss Chromatin Loops Regulate Megakaryocyte/Erythroid Progenitor Expansion by Facilitating HSP70 and GATA1 Induction

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome associated with severe anemia, congenital malformations, and an increased risk of developing cancer. The chromatin-binding special AT-rich sequence-binding protein-1 (SATB1) is downregulated in megakaryocyte/erythroid progenitors (MEPs) in patients and cell models of DBA, leading to a reduction in MEP expansion. Here we demonstrate that SATB1 expression is required for the upregulation of the critical erythroid factors heat shock protein 70 (HSP70) and GATA1 which accompanies MEP differentiation. SATB1 binding to specific sites surrounding the HSP70 genes promotes chromatin loops that are required for the induction of HSP70, which, in turn, promotes GATA1 induction. This demonstrates that SATB1, although gradually downregulated during myelopoiesis, maintains a biological function in early myeloid progenitors.

Automated summary

Diamond Blackfan anemia (DBA) is a genetic bone marrow failure syndrome characterized by severe anemia, congenital malformations, and an increased cancer risk. The downregulation of the SATB1 protein in patients and cell models of DBA leads to a reduction in the expansion of megakaryocyte/erythroid progenitors (MEPs). However, SATB1 is still important for the upregulation of erythroid factors like heat shock protein 70 (HSP70) and GATA1 during MEP differentiation, through its binding to specific sites surrounding the HSP70 genes and promoting chromatin loops necessary for their induction.