Stem Cell Factor SALL4 Represses the Transcriptions of PTEN and SALL1 through an Epigenetic Repressor Complex
Stem Cell Factor SALL4 Represses the Transcriptions of PTEN and SALL1 through an Epigenetic Repressor Complex
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DOI：
10.1371/journal.pone.0005577
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发表时间：
2009-05-18
期刊：
影响因子：
3.7
通讯作者：
Chai, Li
中科院分区：
文献类型：
--
作者：
Lu, Jiayun;Jeong, Hawon;Chai, Li
背景：胚胎干细胞因子SALL4在胚胎发育和白血病发生中起重要作用。这是一个在胚胎干细胞和白血病干细胞中参与自我更新的独特基因。方法/主要发现：为了了解SALL4功能的机制(S)(S)，我们试图通过串联质谱仪鉴定SALL4相关蛋白。在内源性SALL4表达的ESCs和高表达SALL4的293T细胞中，在具有组蛋白脱乙酰酶(HDAC)活性的SALL4免疫复合体中发现了转录抑制因子Mi-2/核小体重塑和去乙酰化酶(NuRD)复合体的成分。在两个潜在的靶基因PTEN和SALL1上测试了SALL4介导的转录调控。染色质免疫沉淀证实这两个基因均为SALL4下游靶基因，经定量逆转录聚合酶链式反应(qRT-PCR)检测，在高表达SALL4的293T细胞中，它们的表达水平均降低。此外，PTEN和SALL1启动子区域的SALL4结合位点被NuRD组分共同占据，这表明SALL4通过与Mi-2/NuRD复合体相互作用而抑制PTEN和SALL1的转录。结论：本研究首次证明干细胞蛋白SALL4通过表观抑制因子Mi-2/NuRD复合体抑制其靶基因PTEN和SALL1的表达。我们的新发现为揭示SALL4在肾脏发育和白血病发生中的作用机制(S)提供了洞察力。
Background: The embryonic stem cell (ESC) factor, SALL4, plays an essential role in both development and leukemogenesis. It is a unique gene that is involved in self-renewal in ESC and leukemic stem cell (LSC).Methodology/Principal Findings: To understand the mechanism(s) of SALL4 function(s), we sought to identify SALL4-associated proteins by tandem mass spectrometry. Components of a transcription repressor Mi-2/Nucleosome Remodeling and Deacetylase (NuRD) complex were found in the SALL4-immunocomplexes with histone deacetylase (HDAC) activity in ESCs with endogenous SALL4 expression and 293T cells overexpressing SALL4. The SALL4-mediated transcriptional regulation was tested on two potential target genes: PTEN and SALL1. Both genes were confirmed as SALL4 downstream targets by chromatin-immunoprecipitation, and their expression levels, when tested by quantitative reverse transcription polymerase chain reaction (qRT-PCR), were decreased in 293T cells overexpressing SALL4. Moreover, SALL4 binding sites at the promoter regions of PTEN and SALL1 were co-occupied by NuRD components, suggesting that SALL4 represses the transcriptions of PTEN and SALL1 through its interactions with the Mi-2/NuRD complex. The in vivo repressive effect( s) of SALL4 were evaluated in SALL4 transgenic mice, where decreased expressions of PTEN and SALL1 were associated with myeloid leukemia and cystic kidneys, respectively.Conclusions/Significance: In summary, we are the first to demonstrate that stem cell protein SALL4 represses its target genes, PTEN and SALL1, through the epigenetic repressor Mi-2/NuRD complex. Our novel finding provides insight into the mechanism(s) of SALL4 functions in kidney development and leukemogenesis.