POGZ Is Required for Silencing Mouse Embryonic β-like Hemoglobin and Human Fetal Hemoglobin Expression
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
Affiliations
Bjorg Gudmundsdottir
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA
Kristbjorn O. Gudmundsson
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA
Kimberly D. Klarmann
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA; Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Bldg. 560/32-31D, 1050 Boyles Street, Frederick, MD 21702, USA
Satyendra K. Singh
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA
Lei Sun
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA
Shweta Singh
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA
Yang Du
Department of Pediatrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
Vincenzo Coppola
Wexner Medical Center, Ohio State University, 460 West 12thAvenue, Columbus, OH 43210, USA
Luke Stockwin
Drug Mechanisms Group, Developmental Therapeutics Program, Leidos Biomedical Research, Inc., National Cancer Institute at Frederick, Frederick, MD 21702, USA
Nhu Nguyen
Department of Pediatrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
Lino Tessarollo
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA
Leifur Thorsteinsson
The Blood Bank, Landspitali University Hospital, Snorrabraut 60, 105 Reykjavik, Iceland
Olafur E. Sigurjonsson
The Blood Bank, Landspitali University Hospital, Snorrabraut 60, 105 Reykjavik, Iceland
Sveinn Gudmundsson
The Blood Bank, Landspitali University Hospital, Snorrabraut 60, 105 Reykjavik, Iceland
Molecular and Clinical Hematology Branch, NHLBI/NIDDK, NIH, Bethesda, MD 20814, USA
Jonathan R. Keller
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560/12-70, 1050 Boyles Street, Frederick, MD 21702, USA; Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Bldg. 560/32-31D, 1050 Boyles Street, Frederick, MD 21702, USA; Corresponding author
Summary: 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. : 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. Keywords: hematopoietic development, erythropoiesis, red cells, globin switching, fetal globin, gene regulation, transcription, sickle cell disease, β-thalassemia
