Journal
CELL REPORTS
Volume 23, Issue 11, Pages 3236-3248Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.05.043
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Funding
- Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]
- intramural research program of the NHLBI, NIH [HL006009-09]
- intramural research program of the NIDDK, NIH [HL006009-09]
- USUHS [R086414217]
- NATIONAL CANCER INSTITUTE [ZICBC011236, ZICBC011265] Funding Source: NIH RePORTER
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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 beta-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 beta-like globin expression without affecting erythroid development. POGZ binds to the Bcl11a promoter and erythroid-specific intragenic regulatory regions. Pogz(+/-) mice show elevated embryonic beta-like globin expression, suggesting that partial reduction of Pogz expression results in persistence of embryonic beta-like globin expression. Knockdown of POGZ in primary human CD34(+) progenitor cell-derived erythroblasts reduces BCL11A expression, a known repressor of embryonic beta-like globin expression, and increases fetal hemoglobin expression. These findings are significant, since new therapeutic targets and strategies are needed to treat beta-globin disorders.
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