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Genome-Wide Analysis Reveals Sall4 to Be a Major Regulator of Pluripotency in Murine-Embryonic Stem Cells

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Genome-Wide Analysis Reveals Sall4 to Be a Major Regulator of Pluripotency in Murine-Embryonic Stem Cells Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells Jianchang Yanga, Li Chaib, Taylor C. Fowlesa, Zaida Alipioa, Dan Xua, Louis M. Finka, David C. Warda,1, and Yupo Maa,1 aDivision of Laboratory Medicine, Nevada Cancer Institute, One Breakthrough Way, Las Vegas, NV 89135; and bDepartment of Pathology, Joint Program in Transfusion Medicine, Brigham and Women’s Hospital/Children’s Hospital Boston, Harvard Medical School, 75 Francis Street, Boston, MA 02115 Contributed by David C. Ward, September 18, 2008 (sent for review June 2, 2008) Embryonic stem cells have potential utility in regenerative medi- signal transduction pathways, and genes relating to epigenetic cine because of their pluripotent characteristics. Sall4, a zinc-finger processes associated with PRCs as well as bivalent histone transcription factor, is expressed very early in embryonic develop- methylations. These observations suggest that Sall4 is an essen- ment with Oct4 and Nanog, two well-characterized pluripotency tial regulator of cell pluripotency and differentiation. regulators. Sall4 plays an important role in governing the fate of stem cells through transcriptional regulation of both Oct4 and Results Nanog. By using chromatin immunoprecipitation coupled to mi- Sall4 Is a Major Transcriptional Regulator in ES Cells. A growing body croarray hybridization (ChIP-on-chip), we have mapped global of evidence has shown that Sall4 plays a vital role in maintaining gene targets of Sall4 to further investigate regulatory processes in ES cell pluripotency and in governing ES cell-fate decisions (9, W4 mouse ES cells. A total of 3,223 genes were identified that were 10, 14, 15). This prompted us to investigate the global down- bound by the Sall4 protein on duplicate assays with high confi- stream targets of Sall4 in mouse ES cells. By using a duplicate dence, and many of these have major functions in developmental set of ChIP-on-chip assays, we performed a global analysis of and regulatory pathways. Sall4 bound approximately twice as Sall4 binding sites in the mouse ES-cell line W4. This cell line was many annotated genes within promoter regions as Nanog and chosen because it was previously used to generate a conditional approximately four times as many as Oct4. Immunoprecipitation Sall4 knockout ES-cell line (9). The majority of transcription revealed a heteromeric protein complex(es) between Sall4, Oct4, factor binding sites in humans are known to occur Ϸ1–2 kb of the and Nanog, consistent with binding site co-occupancies. Decreas- transcription start site (15). Thus, promoter tiling arrays ing Sall4 expression in W4 ES cells decreases the expression levels (NimbleGen, build MM8) spanning 2.5 kb of promoter regions of Oct4, Sox2, c-Myc, and Klf4, four proteins capable of reprogram- (2 kb upstream and 500 bp downstream from the transcription ming somatic cells to an induced pluripotent state. Further, Sall4 start site) were selected for hybridization to chromatin- bound many genes that are regulated in part by chromatin-based immunoprecipitated DNA obtained by using an affinity-purified epigenetic events mediated by polycomb-repressive complexes anti-Sall4 antibody (16). and bivalent domains. This suggests that Sall4 plays a diverse role Successful ChIP assays critically depend on the specificity of in regulating stem cell pluripotency during early embryonic devel- the antibody used. Therefore, we rigorously characterized the opment through integration of transcriptional and epigenetic antibody used in these immunoprecipitation assays. First, west- controls. ern blot analysis was used to compare the Sall4 antibody preparation with a commercially available anti-HA antibody to induced pluripotent stem cells ͉ epigenetic regulation ͉ Oct4 ͉ demonstrate specificity for either WT Sall4 or a Sall4-HA fusion Nanog ͉ Sox2 protein. Initially, in mouse fibroblast cells transfected with Sall4-HA, we were able to detect the fusion protein by using an all4 is a zinc-finger transcription factor that was originally anti-HA antibody, whereas in untransfected fibroblast cells, no Scloned based on sequence homology to Drosophila spalt Sall4 band was detected [supporting information (SI) Fig. S1A, (sal) (1–3). In Drosophila, sal is a homeotic gene essential in the Lanes 0 and 1]. Although no expression was observed in fibro- development of posterior-head and anterior-tail segments (4). blasts, experiments in W4 ES cells were able to detect expression Human SALL4 mutations are associated with the Duane-radial of endogenous Sall4 [Lanes 2 and 3 (14)]. The endogenous band ray syndrome (Okihiro syndrome), a human autosomal- observed in ES cells was also successfully absorbed (Lanes 4 dominant disease involving multiple organ defects (3, 5, 6). Sall4 and 5). homozygous knockout mice die at an early embryonic stage (7, Next we sought to determine whether our antibody was 8). Our group and others have recently shown that mouse Sall4 applicable in ChIP experiments. ChIP-PCR of DNA fragments plays an essential role in maintaining the self-renewal and obtained by using the anti-Sall4 antibody was able to detect pluripotent properties of ES cells and in governing the fate of the enrichment of the peaks identified by the ChIP-on-chip assay. By inner-cell mass through transcriptional modulation of Oct4 (also using heterozygous Sall4 ES cells overexpressing Sall4-HA, known as Pou5f1) and Nanog (8–10). ES cells are derived from the inner cell mass of the developing Author contributions: J.Y. and Y.M. designed research; J.Y., Z.A., and D.X. performed embryo, and ES-cell pluripotency is regulated in part by Oct4, research; J.Y., L.C., T.C.F., Z.A., D.X., L.M.F., D.C.W., and Y.M. analyzed data; and J.Y., L.C., Sox2, and Nanog, as well as through 2 polycomb-repressive T.C.F., L.M.F., D.C.W., and Y.M. wrote the paper. complexes (PRCs) (11, 12). Sall4 is expressed by cells of the early The authors declare no conflict of interest. embryo, exhibiting an expression pattern similar to Oct4 (8, 9). Data deposition: The data reported in this paper have been deposited in the Gene In recent studies, Sall4 has also been used as part of a gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE11305). signature for pluripotency and an enhancer for somatic cell 1To whom correspondence may be addressed. E-mail: [email protected] or yma@ reprogramming (13, 14). However, the complete mechanism nvcancer.org. whereby Sall4 controls pluripotency and differentiation in ES This article contains supporting information online at www.pnas.org/cgi/content/full/ cells is unknown. The studies reported here demonstrate that 0809321105/DCSupplemental. Sall4 interacts with core transcription factors, genes in multiple © 2008 by The National Academy of Sciences of the USA 19756–19761 ͉ PNAS ͉ December 16, 2008 ͉ vol. 105 ͉ no. 50 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809321105 Downloaded by guest on October 1, 2021 immunoprecipitation of the HA-tag identified 88% (23:26) of A the genes identified by the anti-Sall4 antibody (Fig. S1B). This p<0.001 suggests that our anti-Sall4 antibody is both sensitive and specific Cell Communication for the Sall4 protein when used in immunoprecipitation. We Signal Transduction p<0.001 have also used this antibody for immunohistochemistry to detect Sall4 protein in different tissue samples (Fig. S1C) and for flow Nuclear Protein p<0.001 cytometry to identify cell populations corresponding to leukemic p<0.001 blasts in patient bone marrow samples that uniquely express DNA Binding Sall4 [Fig. S1D (16)]. Transcription Regulation p<0.001 Following binding site determination by NimbleGen, the ChIP-on-chip duplicate assays identified roughly 5,200 Sall4- Developmental Protein p<0.001 bound genes in array 1, and 4,400 Sall4-bound genes in array 2. 0 100 200 300 400 500 600 700 The overall false discovery rate was Ͻ0.20. Comparison of the data from arrays 1 and 2 showed that 3,223 gene promoters gave B Organ positive hybridization signals on both arrays. Of the 1,000 genes Development exhibiting the most intense hybridization signals on array 2, 947 Pattern p<0.05 were also positive on array 1. When only the top 200 genes were Specification considered, the concordance rate was 98.5%. In contrast, when Brain p the 800 lowest intensity signals on each array were analyzed, only Development <0.05 37.2% (array 1) and 52.6% (array 2) of the signals were concordant in both assays. Therefore, we selected only the 3,223 050100150200 genes that were positive on both arrays for further analysis. Examples We next validated a subset of the putative Sall4 binding sites C κ Map4k4, Tlr4, Tlr7, Traf2 by using a ChIP PCR strategy. A total of 55 genes were NF- B interrogated. Primer pairs were prepared for a randomly se- Apoptosis Birc2, Birc4, Casp6, Tnf lected set of hybridization positive genes with varying degrees of Wnt/β-catenin Dkk1, Frat1, Tcf4, Wif1 signal intensity. If a selected gene did not initially produce an PTEN Akt3, Casp3, FoxG1, FoxO1 amplicon level above background, a new primer set was designed PDGF Fos, Pitx2, Smad3, Tgfb1 200–300 bases distal to the first primer site, and the quantitative p53 Brca1, Casp6, Ccnd1, Ccnd2 real-time PCR (Q-RT-PCR) assay was repeated. In some cases, TGF-β Abl1, Abl2, Pdgfra, Elk1 a third primer set was used before designating that gene to be a Sonic Hedgehog Dyrk1a, Hhip, Prkaca, Stk36 false positive. In addition, ChIP-PCR using primers located adjacent to true positive loci were shown to give negative 0 5 10 15 20 25 amplification results, further demonstrating the specificity of Fig. 1. Sall4 is a major regulator in mouse ES cells.
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