SALL4 is a key transcription regulator in normal human hematopoiesis.
SALL4 is a key transcription regulator in normal human hematopoiesis.
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DOI：
10.1111/j.1537-2995.2012.03888.x
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发表时间：
2013-05
期刊：
影响因子：
2.9
通讯作者：
Chai L
中科院分区：
文献类型：
--
作者：
Gao C;Kong NR;Li A;Tatetu H;Ueno S;Yang Y;He J;Yang J;Ma Y;Kao GS;Tenen DG;Chai L
干细胞因子SALL 4是一种锌指转录因子。它在维持胚胎干细胞特性方面起着至关重要的作用，在白血病中作为癌基因发挥作用，最近已被提议用于脐带血扩增。SALL 4在正常人造血中发挥作用的机制，包括其靶基因的鉴定，仍需要探索。染色质免疫沉淀，然后微阵列杂交（ChIP芯片）用于映射SALL 4全球基因靶在正常的原代CD 34+细胞。然后将结果与CD 34+细胞中的SALL 4功能研究相关联。已鉴定出超过1，000种潜在的SALL 4下游靶基因，并通过ChIP-qPCR对5%的潜在靶点进行了结合验证。这些包括参与造血分化和自我更新的基因，如HOXA 9，RUNX 1，CD 34和PTEN。在这些细胞中使用shRNA下调SALL 4表达导致体外髓系集落形成能力降低和体内植入受损。此外，HOXA 9被鉴定为正常人造血中的主要SALL 4靶标，并且CD 34+细胞中SALL 4或HOXA 9表达的丧失具有相似的表型。总之，SALL 4是正常人类造血的关键调节因子，其功能机制至少部分通过HOXA 9。未来的研究将确定调节SALL 4/HOXA 9通路是否可用于细胞治疗，如脐带血扩增和/或骨髓移植。
Stem cell factor SALL4 is a zinc finger transcription factor. It plays vital roles in the maintenance of embryonic stem cell properties, functions as an oncogene in leukemia, and has been recently proposed to use for cord blood expansion. The mechanism(s) by which SALL4 functions in normal human hematopoiesis, including identification of its target genes, still need to be explored. Chromatin-immunoprecipitation followed by microarray hybridization (ChIP-chip) was used for mapping SALL4 global gene targets in normal primary CD34+ cells. The results were then correlated with SALL4 functional studies in the CD34+ cells. Over 1,000 potential SALL4 down-stream target genes have been identified, and validation of binding by ChIP-qPCR was performed for 5% of potential targets. These include genes that are involving in hematopoietic differentiation and self-renewal, such as HOXA9, RUNX1, CD34, and PTEN. Down-regulation of SALL4 expression using shRNA in these cells led to decreased in vitro myeloid colony forming abilities and impaired in vivo engraftment. Furthermore, HOXA9 was identified to be a major SALL4 target in normal human hematopoiesis and the loss of either SALL4 or HOXA9 expression in CD34+ cells shared a similar phenotype. Taking together, SALL4 is a key regulator in normal human hematopoiesis and the mechanism of its function is at least in part through the HOXA9. Future study will determine whether modulating the SALL4/HOXA9 pathway can be used in cellular therapy such as cord blood expansion and/or myeloid engraftment.
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