POGZ Is Required for Silencing Mouse Embryonic β-like Hemoglobin and Human Fetal Hemoglobin Expression

Publication date: 12 June 2018
Source:Cell Reports, Volume 23, Issue 11
Author(s): Bjorg Gudmundsdottir, Kristbjorn O. Gudmundsson, Kimberly D. Klarmann, Satyendra K. Singh, Lei Sun, Shweta Singh, Yang Du, Vincenzo Coppola, Luke Stockwin, Nhu Nguyen, Lino Tessarollo, Leifur Thorsteinsson, Olafur E. Sigurjonsson, Sveinn Gudmundsson, Thorunn Rafnar, John F. Tisdale, Jonathan R. Keller
Fetal 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.

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Teaser

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 β-thalassemia.


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