Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Blood. 2012 Nov 15;120(20):4219-28. doi: 10.1182/blood-2011-10-387050. Epub 2012 Sep 14.
In red cell development, the differentiation program directed by the transcriptional regulator GATA1 requires signaling by the cytokine erythropoietin, but the mechanistic basis for this signaling requirement has remained unknown. Here we show that erythropoietin regulates GATA1 through protein kinase D activation, promoting histone deacetylase 5 (HDAC5) dissociation from GATA1, and subsequent GATA1 acetylation. Mice deficient for HDAC5 show resistance to anemic challenge and altered marrow responsiveness to erythropoietin injections. In ex vivo studies, HDAC5(-/-) progenitors display enhanced entry into and passage through the erythroid lineage, as well as evidence of erythropoietin-independent differentiation. These results reveal a molecular pathway that contributes to cytokine regulation of hematopoietic differentiation and offer a potential mechanism for fine tuning of lineage-restricted transcription factors by lineage-specific cytokines.
在红细胞发育过程中，转录调节因子 GATA1 指导的分化程序需要细胞因子促红细胞生成素的信号，但这种信号要求的机制基础仍然未知。在这里，我们表明促红细胞生成素通过蛋白激酶 D 的激活来调节 GATA1，促进组蛋白去乙酰化酶 5（HDAC5）与 GATA1 的解离，随后 GATA1 乙酰化。缺乏 HDAC5 的小鼠对贫血挑战具有抗性，并且骨髓对促红细胞生成素注射的反应发生改变。在离体研究中，HDAC5(-/-)祖细胞显示出增强进入和通过红细胞谱系的能力，以及促红细胞生成素非依赖性分化的证据。这些结果揭示了一个分子途径，有助于细胞因子调节造血分化，并为细胞特异性细胞因子精细调节谱系特异性转录因子提供了一个潜在的机制。
