Abstract
BackgroundThe 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 FindingsTo 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/SignificanceIn 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.
Highlights
The human SAL gene family, SALL1, SALL2, SALL3 and SALL4, was originally cloned on the basis of DNA sequence homology to the Drosophila homeotic gene spalt [1,2,3]
It was observed that the expression level of Phosphatase and Tensin Homolog (PTEN) was decreased 20% in bone marrow (BM) cells of SALL4B transgenic mice compared to litter mate controls (Figure 7F). These findings indicated that the association of SALL4 and Mi2/Nucleosome Remodeling and Deacetylase (NuRD) complex could be related to multiple biological processes, and the inhibition of PTEN and SALL1 expression by SALL4 may at least partially contribute to SALL4 induced acute myeloid leukemia (AML) and cystic kidneys in the transgenic mice
It plays an essential role in the maintenance of pluripotency and self-renewal properties of embryonic stem cells (ESC) by activation of another pluripotency factor, Oct4
Summary
The human SAL gene family, SALL1, SALL2, SALL3 and SALL4, was originally cloned on the basis of DNA sequence homology to the Drosophila homeotic gene spalt [1,2,3]. SAL-related genes have been isolated from Caenorhabditis elegans [6,7], fish [8,9], Xenopus [10,11], mice [12], and humans [1,13] Each of these homologues is expressed during embryonic development, as well as in specific adult tissues. By 10.5 days postcoitum, SALL4 is detectable mainly in the stem/ progenitor populations in various organ systems including the brain and bone marrow of the embryo and later in the adult This may suggest that SALL4 is involved in ESCs and in adult stem cells [19]. It is a unique gene that is involved in self-renewal in ESC and leukemic stem cell (LSC)
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