期刊
CELL REPORTS
卷 23, 期 11, 页码 3236-3248出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.05.043
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资金
- 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
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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