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干细胞因子SALL4通过一种表观遗传抑制复合物抑制PTEN和SALL1的转录。

Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex.

作者信息

Lu Jiayun, Jeong Ha-Won, Kong Nikki, Yang Youyang, Carroll John, Luo Hongbo R, Silberstein Leslie E, Chai Li

机构信息

Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital/Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America.

出版信息

PLoS One. 2009;4(5):e5577. doi: 10.1371/journal.pone.0005577. Epub 2009 May 18.

DOI:10.1371/journal.pone.0005577
PMID:19440552
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2679146/
Abstract

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.

摘要

背景

胚胎干细胞（ESC）因子SALL4在发育和白血病发生过程中均发挥着重要作用。它是一个独特的基因，参与胚胎干细胞和白血病干细胞（LSC）的自我更新。

方法/主要发现：为了解SALL4功能的机制，我们试图通过串联质谱法鉴定与SALL4相关的蛋白质。在具有内源性SALL4表达的胚胎干细胞和过表达SALL4的293T细胞中，在具有组蛋白去乙酰化酶（HDAC）活性的SALL4免疫复合物中发现了转录抑制因子Mi-2/核小体重塑和去乙酰化酶（NuRD）复合物的成分。在两个潜在的靶基因PTEN和SALL1上测试了SALL4介导的转录调控。通过染色质免疫沉淀证实这两个基因均为SALL4的下游靶标，当通过定量逆转录聚合酶链反应（qRT-PCR）检测时，它们在过表达SALL4的293T细胞中的表达水平降低。此外，PTEN和SALL1启动子区域的SALL4结合位点被NuRD成分共同占据，这表明SALL4通过与Mi-2/NuRD复合物相互作用来抑制PTEN和SALL1的转录。在SALL4转基因小鼠中评估了SALL4的体内抑制作用，其中PTEN和SALL1的表达降低分别与髓系白血病和多囊肾有关。

结论/意义：总之，我们首次证明干细胞蛋白SALL4通过表观遗传抑制因子Mi-2/NuRD复合物抑制其靶基因PTEN和SALL1。我们的新发现为SALL4在肾脏发育和白血病发生中的功能机制提供了见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/3eadf98d3ac8/pone.0005577.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/62c07dd22b3a/pone.0005577.g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/9bef0a09b940/pone.0005577.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/1fdf0c4ffabf/pone.0005577.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/b26f7e0a35f8/pone.0005577.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/03918f925375/pone.0005577.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/310228461796/pone.0005577.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/22f006f77745/pone.0005577.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/3eadf98d3ac8/pone.0005577.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/62c07dd22b3a/pone.0005577.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/86d81894bbfc/pone.0005577.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/9bef0a09b940/pone.0005577.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/1fdf0c4ffabf/pone.0005577.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/b26f7e0a35f8/pone.0005577.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/03918f925375/pone.0005577.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/310228461796/pone.0005577.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/22f006f77745/pone.0005577.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7873/2679146/3eadf98d3ac8/pone.0005577.g009.jpg

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