| spalt like transcription factor 4 | OKDB#: 1900 |
| Symbols: | SALL4 | Species: | human | ||
| Synonyms: | DRRS, HSAL4, ZNF797 | Locus: | 20q13.2 in Homo sapiens |
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| General Comment |
The region-specific homeotic gene spalt (sal) of Drosophila is an essential genetic component required for the specification of posterior head and anterior tail as opposed to trunk segments. Sal encodes a protein that contains 3 distinct DNA-binding zinc finger domains and alanine- and glutamine-rich domains that are commonly found in transcription factors.
Roles of Sall4 in the generation of pluripotent stem cells from blastocysts and fibroblasts. Tsubooka N et al. Pluripotency of embryonic stem (ES) cells is maintained by a network consisting of multiple transcription factors, including Oct3/4, Sox2, Nanog, Klf4 and Sall4. Among these factors, the forced expressions of Oct3/4, Sox2 and Klf4 are sufficient to reprogram fibroblasts into induced pluripotent stem (iPS) cells. The current study analyzed the role of Sall4 during the generation of ES cells and iPS cells. The mouse Sall4 gene was deleted by homologous recombination. Sall4-null embryos died shortly after implantation, as has been reported. ES-like cell lines can be established from Sall4-null blastocysts, albeit with a lower efficiency and a slower time course. The knockdown of Sall4 significantly decreased the efficiency of iPS cell generation from mouse fibroblasts. Furthermore, retroviral transduction of Sall4 significantly increased the efficiency of iPS cell generation in mouse and some human fibroblast lines. These results demonstrated that Sall4 plays positive roles in the generation of pluripotent stem cells from blastocysts and fibroblasts.
Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Zhang J et al. Embryonic stem (ES) cells are pluripotent cells that can self-renew or differentiate into many cell types. A unique network of transcription factors and signalling molecules are essential for maintaining this capability. Here, we report that a spalt family member, Sall4, is required for the pluripotency of ES cells. Similarly to Oct4, a reduction in Sall4 levels in mouse ES cells results in respecification, under the appropriate culture conditions, of ES cells to the trophoblast lineage. Sall4 regulates transcription of Pou5f1 which encodes Oct4. Sall4 binds to the highly conserved regulatory region of the Pou5f1 distal enhancer and activates Pou5f1 expression in vivo and in vitro. Microinjection of Sall4 small interfering (si) RNA into mouse zygotes resulted in reduction of Sall4 and Oct4 mRNAs in preimplantation embryos and significant expansion of Cdx2 expression into the inner cell mass. These results demonstrate that Sall4 is a transcriptional activator of Pou5f1 and has a critical role in the maintenance of ES cell pluripotency by modulating Oct4 expression. The data also indicates that Sall4 is important for early embryonic cell-fate decisions.
NCBI Summary: This gene encodes a zinc finger transcription factor thought to play a role in the development of abducens motor neurons. Defects in this gene are a cause of Duane-radial ray syndrome (DRRS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015] |
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| General function |
Nucleic acid binding, DNA binding, Transcription factor
, Epigenetic modifications |
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| Comment | stemness///Maternal Sall4 Is Indispensable for Epigenetic Maturation of Mouse Oocytes. Xu K et al. (2016) Splat-like 4 (Sall4) plays important roles in maintaining pluripotency of embryonic stem cells and in various developmental processes. Here, we find that Sall4 is highly expressed in oocytes and early embryos. To investigate the roles of SALL4 in oogenesis, we generated Sall4 maternal specific knockout mice by using CRISPR/Cas9 system. And we find that the maternal deletion of Sall4 causes developmental arrest of oocytes at germinal vesicle stage with non-surrounded nucleus and the subsequent meiosis resumption is prohibited. We further discover that the loss of maternal Sall4 causes failure in establishment of DNA methylation in oocytes. Furthermore, we find that Sall4 modulates H3K4me3 and H3K27me3 modifications by regulating the expression of key histone demethylases coding genes Kdm5b, Kdm6a and Kdm6b in oocytes. Moreover, we demonstrate that the aberrant H3K4me3 and H3K27me3 cause mis-expression of genes that are critical for oocytes maturation and meiosis resumption. Taken together, our study explores a pivotal role of Sall4 in regulating epigenetic maturation of mouse oocytes.////////////////// | ||||
| Cellular localization | Nuclear | ||||
| Comment | |||||
| Ovarian function |
Oocyte maturation, Early embryo development
, Pluripotent cell derivation |
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| Comment | High-efficiency stem cell fusion-mediated assay reveals Sall4 as an enhancer of reprogramming. Wong CC et al. Several methods allow reprogramming of differentiated somatic cells to embryonic stem cell-like cells. However, the process of reprogramming remains inefficient and the underlying molecular mechanisms are poorly understood. Here, we report the optimization of somatic cell fusion with embryonic stem cells in order to provide an efficient, quantitative assay to screen for factors that facilitate reprogramming. Following optimization, we achieved a reprogramming efficiency 15-590 fold higher than previous protocols. This allowed observation of cellular events during the reprogramming process. Moreover, we demonstrate that overexpression of the Spalt transcription factor, Sall4, which was previously identified as a regulator of embryonic stem cell pluripotency and early mouse development, can enhance reprogramming. The reprogramming activity of Sall4 is independent of an N-terminal domain implicated in recruiting the nucleosome remodeling and deacetylase corepressor complex, a global transcriptional repressor. These results indicate that improvements in reprogramming assays, including fusion assays, may allow the systematic identification and molecular characterization of enhancers of somatic cell reprogramming. Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages. Lim CY et al. Stem cells self-renew or differentiate under the governance of a stem-cell-specific transcriptional program, with each transcription factor orchestrating the activities of a particular set of genes. Here we demonstrate that a single transcription factor is able to regulate distinct core circuitries in two different blastocyst-derived stem cell lines, embryonic stem cells (ESCs) and extraembryonic endoderm (XEN) cells. The transcription factor Sall4 is required for early embryonic development and for ESC pluripotency. Sall4 is also expressed in XEN cells, and depletion of Sall4 disrupts self-renewal and induces differentiation. Genome-wide analysis reveals that Sall4 is regulating different gene sets in ESCs and XEN cells, and depletion of Sall4 targets in the respective cell types induces differentiation. With Oct4, Sox2, and Nanog, Sall4 forms a crucial interconnected autoregulatory network in ESCs. In XEN cells, Sall4 regulates the key XEN lineage-associated genes Gata4, Gata6, Sox7, and Sox17. Our findings demonstrate how Sall4 functions as an essential stemness factor for two different stem cell lines. | ||||
| Expression regulated by | |||||
| Comment | |||||
| Ovarian localization | Oocyte | ||||
| Comment | SALL4 is one out of four human homologues of the DROSOPHILA region-specific homeotic gene SPALT(SAL). Heterozygous mutations of SALL4 on chromosome 20q13.13--> q13.2 cause the autosomal dominant Okihiro syndrome which is characterized by radial limb defects, Duane anomaly and hearing loss. Kohlhase J, et a have partially cloned the murine homologue of this gene, named SALL4, and completed the coding sequence by comparison to available EST and genomic sequences in the GenBank database. This comparison also revealed the chromosomal location of SALL4 on mouse chromosome 2H3 and suggested that a predicted testis expressed gene TEX20 at the very same locus is most likely not a gene on its own but part of the SALL4 3' UTR. We analyzed the expression of SALL4 during early embryogenesis by whole mount in situ hybridization and in the adult mouse by Northern blotting. In adult tissues, SALL4 expression is only found in testis and ovary. During embryonic development, SALL4 expression is widespread in early embryos and becomes gradually confined to the head region and the primitive streak. Prominent expression in the developing midbrain, branchial arches and the limbs suggests an important function of SALL4 during development of these structures as expected from the observation in Okihiro syndrome patients. Genomewide discovery and classification of candidate ovarian fertility genes in the mouse. Gallardo TD et al. Female infertility syndromes are among the most prevalent chronic health disorders in women, but their genetic basis remains unknown because of uncertainty regarding the number and identity of ovarian factors controlling the assembly, preservation, and maturation of ovarian follicles. To systematically discover ovarian fertility genes en masse, we employed a mouse model (Foxo3) in which follicles are assembled normally but then undergo synchronous activation. We developed a microarray-based approach for the systematic discovery of tissue-specific genes and, by applying it to Foxo3 ovaries and other samples, defined a surprisingly large set of ovarian factors (n = 348, approximately 1% of the mouse genome). This set included the vast majority of known ovarian factors, 44% of which when mutated produce female sterility phenotypes, but most were novel. Comparative profiling of other tissues, including microdissected oocytes and somatic cells, revealed distinct gene classes and provided new insights into oogenesis and ovarian function, demonstrating the utility of our approach for tissue-specific gene discovery. This study will thus facilitate comprehensive analyses of follicle development, ovarian function, and female infertility. This is an oocyte-specific gene. | ||||
| Follicle stages | |||||
| Comment | Microarray Analyses of Newborn Mouse Ovaries Lacking Nobox. Choi Y et al. Nobox is a homeobox gene expressed in oocytes and critical in oogenesis. Nobox deficiency leads to rapid loss of postnatal oocytes. Early oocyte differentiation is poorly understood. We hypothesized that lack of Nobox perturbs global expression of genes preferentially expressed in oocytes as well as microRNAs. We compared Nobox knockout and wild type ovaries using Affymetrix 430 2.0 microarray platform. We discovered that 28 out of 38 (74%) of the genes down-regulated more than five fold in the absence of Nobox were preferentially expressed in oocytes, while only 5 out of 33 (15%) of genes up-regulated more than five fold in the absence of Nobox, were preferentially expressed in oocytes. Protein binding microarray helped identify nucleotide motifs that NOBOX binds, and that several down-regulated genes contain within putative promoter regions. MicroRNA population in newborn ovaries deficient of Nobox, was largely unaffected. Genes whose proteins are predicted to be secreted, but previously unknown to be significantly expressed in early oogenesis, were down regulated in Nobox knockouts and included astacin-like metalloendopeptidase (Astl), Jagged 1 (Jag1), oocyte secreted protein 1 (Oosp1), fetuin beta (Fetub) and R-spondin 2 (Rspo2). In addition, pluripotency associated genes, Pou5f1 and Sall4 are drastically down-regulated in Nobox deficient ovaries, while testes determining gene Dmrt1 is over-expressed. Our findings indicate that Nobox is likely an activator of oocyte-specific gene expression, and suggest that oocyte plays an important role in suppressing expression of male determining genes such as Dmrt1. | ||||
| Phenotypes |
POF (premature ovarian failure) |
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| Mutations |
4 mutations
Species: human
Species: mouse
Species: human
Species: mouse
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
| Links |
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| created: | July 2, 2003, 5:24 p.m. | by: |
hsueh email:
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| last update: | Feb. 28, 2020, 1:59 p.m. | by: | hsueh email: |
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