Abstract
SUMMARYFetal globin genes are transcriptionally silenced during embryogenesis through hemoglobin switching. Strategies to derepress fetal globin expression in the adult could alleviate symptoms in sickle cell disease and β-thalassemia. We identified a zinc-finger protein, pogo transposable element with zinc-finger domain (POGZ), expressed in hematopoietic progenitor cells. Targeted deletion of Pogz in adult hematopoietic cells in vivo results in persistence of embryonic β-like globin expression without affecting erythroid development. POGZ binds to the Bcl11a promoter and erythroid-specific intragenic regulatory regions. Pogz+/− mice show elevated embryonic β-like globin expression, suggesting that partial reduction of Pogz expression results in persistence of embryonic β-like globin expression. Knockdown of POGZ in primary human CD34+ progenitor cell-derived erythroblasts reduces BCL11A expression, a known repressor of embryonic β-like globin expression, and increases fetal hemoglobin expression. These findings are significant, since new therapeutic targets and strategies are needed to treat β-globin disorders.
Highlights
We identified a zinc-finger protein, pogo transposable element with zinc-finger domain (POGZ), expressed in hematopoietic progenitor cells
POGZ binds to the Bcl11a promoter and erythroid-specific intragenic regulatory regions
POGZ is expressed in KG1 cells, and POGZ RNA and protein levels are decreased during differentiation, suggesting that POGZ may function in hematopoietic cells (Figures 1A and 1B)
Summary
Gudmundsdottir et al show that POGZ represses embryonic globin gene expression in mouse and human erythroid cells, in part by regulating Bcl11a expression in vitro and in vivo. The molecular pathways regulated by POGZ may represent potential therapeutic targets to increase fetal globin expression in patients with sickle cell disease and b-thalassemia. Highlights d Pogz is highly expressed in mouse megakaryocyte erythroid progenitors. Gudmundsdottir et al, 2018, Cell Reports 23, 3236–3248 June 12, 2018 a 2018 The Authors.
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