Affinage

SALL4

Sal-like protein 4 · UniProt Q9UJQ4

Length
1053 aa
Mass
112.2 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SALL4 is a zinc-finger transcription factor that serves as a master regulator of pluripotency, stem cell self-renewal, and lineage specification across embryonic, germline, and hematopoietic compartments. It maintains the pluripotent state by physically interacting with Oct4, Sox2, and Nanog to co-occupy and activate enhancers of core pluripotency genes (Pou5f1, Nanog), while repressing differentiation and tumor-suppressor genes (PTEN, SALL1, Foxl1) through recruitment of the NuRD/HDAC co-repressor complex via a structurally defined N-terminal RBBp4-binding motif; this dual activator–repressor function is essential for somatic reprogramming and prevention of precocious neural differentiation (PMID:16980957, PMID:19440552, PMID:27471257, PMID:37208322, PMID:29976840). Its AT-rich DNA-binding zinc-finger cluster is required for genome-wide chromatin occupancy, and mutation of this domain phenocopies Sall4 nulls including embryonic lethality (PMID:33406384). SALL4 is post-translationally regulated by sumoylation, which stabilizes the protein and modulates transcriptional output, and by CRBN-dependent ubiquitin-mediated proteasomal degradation induced by thalidomide/IMiDs — establishing SALL4 degradation as the mechanism underlying thalidomide teratogenicity (PMID:23012367, PMID:32071327).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Establishing SALL4 as a direct transcriptional activator of the core pluripotency gene Oct4 answered how the inner cell mass maintains Oct4 expression and resolved that SALL4 occupies the Pou5f1 distal enhancer to prevent trophoblast fate.

    Evidence ChIP, luciferase reporter, siRNA knockdown in mouse zygotes

    PMID:16980957

    Open questions at the time
    • Whether SALL4 activates Oct4 independently or requires cofactors was unresolved
    • Mechanism of transcriptional activation (chromatin remodeling vs. polymerase recruitment) unknown
  2. 2006 High

    Demonstrating that SALL4 physically interacts with Nanog and that the two factors co-occupy each other's enhancers revealed a positive autoregulatory loop that stabilizes the pluripotency network, while identification of SALL4 as a Wnt/TCF-LEF target gene placed it downstream of a major developmental signaling pathway.

    Evidence Affinity purification/MS, Co-IP, GST pulldown, ChIP (SALL4-Nanog); luciferase reporter with TCF/LEF site mutagenesis (Wnt regulation)

    PMID:16840789 PMID:16899215

    Open questions at the time
    • Whether Wnt-mediated SALL4 induction is the primary mechanism activating SALL4 in vivo remained untested
    • Stoichiometry of the SALL4-Nanog complex unknown
  3. 2008 High

    Genome-wide binding maps and genetic loss-of-function showed SALL4 occupies thousands of targets and is essential for epiblast and primitive endoderm but not trophoblast, establishing context-dependent regulatory circuits distinct between ES and extraembryonic endoderm cells.

    Evidence ChIP-on-chip/ChIP-seq in ES and XEN cells, conditional knockout mice, stem cell derivation assays

    PMID:17060609 PMID:18804426 PMID:19060217

    Open questions at the time
    • How SALL4 switches between activating and repressive modes in different lineages was unknown
    • Whether SALL4 isoforms contribute to lineage-specific programs was unresolved
  4. 2009 High

    Identification of SALL4 as a recruiter of the NuRD/HDAC co-repressor complex that silences PTEN and SALL1 explained how SALL4 functions as a transcriptional repressor and linked this mechanism to myeloid leukemia and cystic kidney phenotypes.

    Evidence Co-IP/tandem mass spectrometry of SALL4 immunocomplexes, ChIP on PTEN and SALL1 promoters, HDAC activity assay, transgenic mouse model

    PMID:19440552

    Open questions at the time
    • Whether NuRD is required for all SALL4-mediated repression or only a subset of targets was unknown
    • Structural basis of the SALL4-NuRD interaction was unresolved
  5. 2010 High

    Discovery that Sall4a and Sall4b isoforms form homo- and heterodimers, occupy distinct but overlapping genomic sites, and differ in capacity to maintain pluripotency (Sall4b sufficient, Sall4a insufficient alone) revealed isoform-specific division of labor.

    Evidence Isoform-specific ChIP-seq, Co-IP, ES cell rescue experiments

    PMID:20837710

    Open questions at the time
    • Structural basis for differential DNA binding of isoforms unknown
    • How isoform ratio is regulated during differentiation was unresolved
  6. 2011 High

    Showing that SALL4 and PLZF physically interact and mutually redistribute each other on chromatin in spermatogonia established a reciprocal chromatin-sequestration mechanism controlling the self-renewal-to-differentiation switch in male germline stem cells.

    Evidence Co-IP, ChIP, conditional knockout mice, gene expression analysis in spermatogonial progenitor cells

    PMID:22385656

    Open questions at the time
    • Whether this sequestration mechanism operates in other stem cell compartments was unknown
    • Genome-wide redistribution of SALL4 by PLZF was not mapped
  7. 2012 High

    Identification of sumoylation sites on SALL4B and demonstration that sumoylation stabilizes the protein, modulates its chromatin association, and is required for full transcriptional activity established the first post-translational regulatory mechanism for SALL4.

    Evidence Site-directed mutagenesis of four lysines, mass spectrometry, subcellular fractionation, reporter assays, RNAi rescue in ES cells

    PMID:23012367

    Open questions at the time
    • Identity of the SUMO E3 ligase for SALL4 was unknown
    • Whether sumoylation is regulated during differentiation was untested
  8. 2013 High

    Demonstrating that SALL4 cooperates with MLL at the HOXA9 promoter via physical interaction and co-occupancy with activating H3K4me3 marks explained how SALL4 drives leukemogenic gene expression programs, while peptide disruption of the SALL4-NuRD interface validated PTEN de-repression as a therapeutic vulnerability in SALL4-expressing cancers.

    Evidence ChIP, Co-IP, bone marrow transplantation leukemia model (SALL4-MLL); peptide competition, xenograft models, PTEN inhibitor rescue (SALL4-NuRD-PTEN)

    PMID:23287862 PMID:23758232 PMID:24051379

    Open questions at the time
    • Whether SALL4 cooperates with MLL independent of NuRD was unresolved
    • In vivo pharmacokinetics of NuRD-disrupting peptides were not established
  9. 2015 High

    Revealing that SALL4 rapidly localizes to DNA double-strand breaks, stabilizes the MRN complex through direct Rad50 interaction, and is required for ATM activation uncovered an unexpected non-transcriptional role for SALL4 in the DNA damage response.

    Evidence Live-cell imaging, FRAP, Co-IP with Rad50 and Baf60a, ATM phosphorylation assays in ES cells

    PMID:25733712

    Open questions at the time
    • Whether SALL4's DSB role is specific to ES cells or general was unknown
    • Structural basis of SALL4-Rad50 interaction unresolved
    • Whether SALL4 DNA damage function is independent of its transcriptional role was unclear
  10. 2016 High

    Genome-wide analysis in Sall4 knockout ES cells showed SALL4 acts primarily at enhancers to prevent precocious neural gene activation, and critically, that although SALL4 physically associates with NuRD, it does not recruit NuRD to chromatin — challenging the prevailing model of SALL4 as a NuRD-dependent repressor.

    Evidence ChIP-seq and proteomics in Sall4 KO ES cells, NuRD recruitment assays

    PMID:27471257

    Open questions at the time
    • How to reconcile this with functional NuRD-dependence shown in cancer and spermatogonia was unclear
    • Identity of the actual repressive mechanism at neural enhancers was unknown
  11. 2018 High

    Solving the crystal structure of the SALL4 N-terminal peptide bound to RBBp4 and engineering a high-affinity competitive peptide (23 nM) that converts SALL4 from repressor to activator provided the structural basis for the NuRD interaction and a pharmacological strategy to de-repress PTEN in tumors.

    Evidence X-ray crystallography at 2.7 Å, surface plasmon resonance, systematic peptide truncation/mutagenesis, xenograft tumor model

    PMID:29976840

    Open questions at the time
    • Whether small molecules can mimic the peptide antagonist was unknown
    • Whether other NuRD-binding transcription factors share this structural interface was untested
  12. 2020 High

    Demonstrating that thalidomide/IMiDs induce SALL4 degradation via the CRBN-CRL4 E3 ubiquitin ligase, and that point mutations in either CRBN or SALL4 block degradation and rescue mesendoderm differentiation, established CRBN-dependent SALL4 destruction as the molecular mechanism of thalidomide teratogenicity.

    Evidence CRBN V388I and SALL4 G416A knock-in hiPSCs, proteasome inhibitor treatment, mesendoderm differentiation assays

    PMID:32071327

    Open questions at the time
    • Structural basis of the SALL4-thalidomide-CRBN ternary complex was not determined
    • Whether SALL4 degradation alone fully accounts for all limb teratogenicity phenotypes was uncertain
  13. 2021 High

    Structure-function analysis of the SALL4 AT-rich DNA-binding zinc-finger cluster showed it is essential for genome-wide chromatin occupancy and that its loss causes premature derepression of AT-rich neural genes, establishing the DNA-binding mechanism underlying SALL4's anti-differentiation function.

    Evidence Zinc-finger mutagenesis, ChIP-seq, RNA-seq, mouse knock-in genetics

    PMID:33406384

    Open questions at the time
    • Whether AT-richness fully explains target selectivity or additional sequence features contribute was unknown
    • How AT-binding cooperates with cofactor interactions was unresolved
  14. 2023 High

    Showing that SALL4's N-terminal NuRD-interacting motif is essential for chromatin closing during somatic reprogramming, and that grafting this motif onto a non-reprogramming factor partially rescues iPSC generation, reconciled the ES cell finding (NuRD-independent) with a functional NuRD requirement in the reprogramming context.

    Evidence N-terminal motif mutagenesis/deletion, domain-swap onto Jdp2, ATAC-seq, iPSC reprogramming assays

    PMID:37208322

    Open questions at the time
    • Whether NuRD recruitment is required transiently or throughout reprogramming was unclear
    • Which specific NuRD subunits are essential for this chromatin-closing function was not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how SALL4's NuRD-dependent and NuRD-independent transcriptional activities are partitioned across cell types; the structural basis of the SALL4-CRBN-thalidomide ternary complex; and whether SALL4's DNA damage response function is mechanistically separable from its transcriptional role.
  • Full structural characterization of SALL4-CRBN-IMiD ternary complex lacking
  • Context-dependent rules governing NuRD-dependent vs. NuRD-independent repression undefined
  • Whether SALL4 DSB function operates outside stem cells not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-4839726 Chromatin organization 4 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 1
Partners
HDAC2MLLNANOGPLZFPOU5F1RAD50RBBP4SOX2
Complex memberships
NuRD/Mi-2 complexOct4-Sox2-Nanog-Sall4 pluripotency complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Sall4 directly binds the highly conserved distal enhancer region of the Pou5f1 (Oct4) gene and transcriptionally activates Oct4 expression in vivo and in vitro; knockdown of Sall4 in mouse zygotes reduced both Sall4 and Oct4 mRNAs and expanded Cdx2 expression into the inner cell mass, demonstrating that Sall4 is a transcriptional activator of Oct4 required for ES cell pluripotency. ChIP, luciferase reporter assay, siRNA microinjection into zygotes, in vitro transcription assay Nature cell biology High 16980957
2006 Sall4 physically interacts with Nanog (confirmed by affinity purification/MS, Co-IP, and GST pulldown) and co-occupies Nanog and Sall4 enhancer regions in living ES cells; knockdown of either factor reduces the other's enhancer activity, indicating a positive autoregulatory loop. Affinity purification coupled to LC-MS/MS, Co-immunoprecipitation, GST pulldown, ChIP The Journal of biological chemistry High 16840789
2006 SALL4 promoter contains a consensus TCF/LEF-binding site; LEF1 and TCF4E directly activate the SALL4 promoter, and mutation of the TCF/LEF-binding site reduces promoter activation, demonstrating SALL4 is a direct transcriptional target of canonical Wnt signaling. Promoter cloning, luciferase reporter assay, site-directed mutagenesis of TCF/LEF binding site Biochemical and biophysical research communications Medium 16899215
2006 In zebrafish, sall4 acts genetically downstream of tbx5 and is required for pectoral fin (forelimb) outgrowth, placing sall4 in the tbx5 pathway during limb development. Genetic epistasis in zebrafish (morpholino knockdown, overexpression) Development (Cambridge, England) Medium 16501170
2008 Sall4 is cell-autonomously required for development of epiblast and primitive endoderm from the inner cell mass; Sall4-deficient blastocysts cannot give rise to embryonic or extraembryonic endoderm stem cell lines, whereas trophoblast lineage development is unaffected. Conditional knockout mice, blastocyst stem cell derivation assays Proceedings of the National Academy of Sciences of the United States of America High 17060609
2008 Genome-wide ChIP-on-chip mapping identified >3,200 Sall4 target genes in mouse ES cells; Sall4 forms a heteromeric protein complex with Oct4 and Nanog (confirmed by co-IP), and decreasing Sall4 reduces expression of Oct4, Sox2, c-Myc, and Klf4. ChIP-on-chip, Co-immunoprecipitation, RNAi knockdown with expression profiling Proceedings of the National Academy of Sciences of the United States of America High 19060217
2008 Sall4 regulates distinct gene sets in ES cells versus extraembryonic endoderm (XEN) cells; in ES cells Sall4 forms an autoregulatory network with Oct4, Sox2, and Nanog, while in XEN cells it regulates Gata4, Gata6, Sox7, and Sox17, demonstrating context-dependent transcriptional circuitry. Genome-wide ChIP-seq/ChIP-chip, siRNA knockdown, gene expression profiling in two distinct stem cell lines Cell stem cell High 18804426
2008 Compound Sall1/Sall4 and Sall2/Sall4 mutant mice show significantly increased neural tube defects, and SALL1, SALL2, and SALL4 proteins all co-localize in the nucleus in vitro, suggesting redundant nuclear functions in neurulation. Compound knockout mouse genetics, nuclear co-localization (immunofluorescence) The American journal of pathology Medium 18818376
2009 SALL4 associates with the Mi-2/NuRD (Nucleosome Remodeling and Deacetylase) complex, identified by tandem mass spectrometry from SALL4 immunocomplexes; this complex has HDAC activity. SALL4 binds the promoter regions of PTEN and SALL1 (by ChIP) and represses their transcription through the NuRD complex; in SALL4 transgenic mice, decreased PTEN and SALL1 expression is associated with myeloid leukemia and cystic kidneys, respectively. Co-immunoprecipitation, tandem mass spectrometry, HDAC activity assay, ChIP, qRT-PCR, transgenic mouse model PloS one High 19440552
2010 Sall4 exists as two isoforms (Sall4a and Sall4b) that form homodimers and heterodimers with each other and each interacts with Nanog; Sall4b (but not Sall4a) preferentially binds highly expressed loci and can alone maintain the pluripotent state, though incompletely, while Sall4a and Sall4b have overlapping but distinct genome-wide binding sites differing in epigenetic marks. Genome-wide location analysis (ChIP-seq), Co-immunoprecipitation, isoform-specific ES cell rescue experiments Molecular and cellular biology High 20837710
2010 SALL4 and OCT4 form a bidirectional transcriptional feedback loop: SALL4 activates OCT4 expression and OCT4 activates SALL4, while SALL4 also strongly self-represses its own promoter and represses promoters of SALL1 and SALL3, antagonizing OCT4-mediated activation of those genes. Luciferase reporter assay, ChIP, qRT-PCR, co-transfection PloS one Medium 20505821
2011 In differentiating spermatogonial progenitor cells (SPCs), Sall4 physically interacts with Plzf (by Co-IP), sequesters Plzf to non-cognate chromatin domains to de-repress Kit expression (a Plzf target required for differentiation), while Plzf reciprocally antagonizes Sall4 by displacing it from cognate chromatin to induce Sall1 expression. Co-immunoprecipitation, ChIP, genetic loss-of-function (conditional knockout mice), gene expression analysis Cell stem cell High 22385656
2012 Sall4 directly interacts with Sox2 and Oct-3/4 (confirmed by Co-IP), and co-occupies Oct-Sox composite elements in mouse ES cells (by ChIP); Sall4 overexpression increases reporter activity driven by Oct-Sox elements from Pou5f1 and Nanog promoters. Co-immunoprecipitation, ChIP, luciferase reporter assay, microarray The Journal of biological chemistry High 23269686
2012 SALL4B is modified by sumoylation at lysine residues 156, 316, 374, and 401; sumoylation is independent of ubiquitination, stabilizes the protein, affects its subcellular localization (SUMO-deficient SALL4B enriched in chromatin fraction), and is required for full transcriptional activation/repression activity and rescue of OCT4 and SOX2 expression. Site-directed mutagenesis, mass spectrometry, reporter assays, RNAi rescue experiments, subcellular fractionation The Journal of biological chemistry High 23012367
2013 SALL4 binds the promoter of the HOXA9 gene in leukemic cells (by ChIP), interacts with MLL (by Co-IP), and co-occupies the HOXA9 promoter with MLL, leading to enrichment of activating histone marks (H3K4me3); downregulation of HoxA9 in SALL4B leukemic cells reduces replating capacity and delays AML development. ChIP, Co-immunoprecipitation, shRNA knockdown, bone marrow transplantation mouse model, histone modification analysis The Journal of clinical investigation High 24051379
2013 A peptide that competes with SALL4 for binding to the HDAC (NuRD) complex reverses SALL4-mediated PTEN repression, leading to death of SALL4-expressing leukemic cells in vitro and in vivo in xenograft models; this effect is rescued by a PTEN inhibitor, confirming PTEN as the relevant target. Peptide competition assay, HDAC activity assay, ChIP, xenograft mouse model, RNAi comparison Blood High 23287862
2013 In hepatocellular carcinoma, blocking SALL4-corepressor (NuRD/HDAC) interactions releases suppression of PTEN, inhibiting tumor formation in xenograft models, establishing that SALL4 drives HCC tumorigenicity at least in part by epigenetic silencing of PTEN. Loss-of-function studies (RNAi), peptide blockade of SALL4-corepressor interaction, in vivo xenograft assay The New England journal of medicine High 23758232
2013 An Oct4-Sall4-Nanog network governs pre-implantation mouse embryo development; morpholino-mediated knockdown of each factor followed by transcriptome analysis defined their regulons, including a set of metabolism/transport genes regulated in embryos but not ES cells. DNMT3b, controlled by these factors and miR-290-295, buffers embryos against gene expression noise. Morpholino knockdown in embryos, single-embryo and single-blastomere transcriptome analysis, genetic epistasis Molecular systems biology Medium 23295861
2015 Sall4 is required for primordial germ cell (PGC) specification; conditional inactivation of Sall4 during PGC specification leads to apoptosis and failure of PGC translocation from mesoderm to endoderm, with derepression of somatic program genes Hoxa1 and Hoxb1 while stem cell program activation is intact. Sall4 binds these somatic gene loci (ChIP) and likely recruits a histone deacetylase repressor complex with Prdm1. Conditional knockout mice, ChIP, gene expression analysis, cell fate tracking Stem cells (Dayton, Ohio) High 25263278
2015 Sall4 is required for activating ATM-dependent DNA double-strand break (DSB) responses in mouse ES cells; Sall4 rapidly localizes to DSB sites, interacts with Rad50 (Co-IP), stabilizes the Mre11-Rad50-Nbs1 (MRN) complex for ATM recruitment and activation, and interacts with Baf60a (SWI/SNF complex member) which recruits Sall4 to DSB sites. Live-cell imaging (localization to DSB sites), Co-immunoprecipitation, siRNA knockdown, ATM activation assays, FRAP The Journal of cell biology High 25733712
2016 Sall4 is an enhancer-binding protein that prevents precocious neural gene expression in ES cells; although a fraction of Sall4 protein physically associates with the NuRD complex, Sall4 neither recruits NuRD to chromatin nor regulates transcription via NuRD — free Sall4 protein regulates transcription independently of NuRD. Sall4 knockout ES cells, ChIP-seq, proteomics (mass spectrometry), NuRD recruitment assays, gene expression profiling Development (Cambridge, England) High 27471257
2016 In undifferentiated spermatogonia, SALL4 and PLZF bind 1295 shared gene targets; SALL4 preferentially binds intronic sites (including DMRT1 differentiation factor motifs) while PLZF binds promoters; knockdown of either factor suppresses mRNA levels of both unique and shared target genes involved in SSC self-renewal and differentiation. ChIP-seq in mouse THY1+ spermatogonia, motif analysis, shRNA knockdown with expression profiling Development (Cambridge, England) High 27068105
2017 SALL4 promotes glycolysis and open chromatin by recruiting ubiquitin E3 ligase CUL4B to heterochromatin protein 1α (HP1α), destabilizing HP1α; loss of SALL4 reduces Glut1 expression and inhibits glycolysis; restoring Glut1 expression rescues impaired DNA damage response in SALL4-deficient cancer cells, establishing a SALL4-HP1α-Glut1 axis. Co-immunoprecipitation, ubiquitination assay, ChIP, siRNA knockdown, Glut1 rescue experiments Oncogene Medium 28759035
2017 In undifferentiated spermatogonia, SALL4 associates with the NuRD co-repressor and represses tumor suppressor genes Foxl1 and Dusp4; inducible SALL4 knockout leads to long-term functional decline of undifferentiated spermatogonia, and aberrant Foxl1 activation inhibits cell growth and survival while DUSP4 suppresses self-renewal pathways. Inducible knockout mouse models, Co-immunoprecipitation (NuRD), gene expression analysis, functional spermatogonial assays Stem cell reports High 28867346
2017 SALL4 is required for MLL-AF9-induced leukemic transformation; loss of SALL4 induces apoptosis and G1 arrest in MLL-AF9 cells. SALL4 physically interacts with DOT1L and LSD1/KDM1A (Co-IP) and co-binds MLL-AF9 target gene promoters, affecting H3K79me2/3 and H3K4me3 histone marks to regulate their transcription. Tamoxifen-inducible Cre-mediated knockout, retroviral transduction/transplantation, ChIP-seq, Co-immunoprecipitation, histone modification analysis Journal of hematology & oncology High 28974232
2018 Crystal structure of SALL4(1–12) N-terminal peptide complexed with RBBp4 (NuRD chaperone subunit) at 2.7 Å resolution was determined; systematic truncation and amino acid substitution defined an FFW peptide with 23 nM affinity that antagonizes SALL4-NuRD interaction; disrupting this interaction converts SALL4 from dual repressor-activator to singular activator mode, upregulating PTEN and inhibiting xenograft tumor growth by 85%. Crystal structure determination, peptide design with mutagenesis, surface plasmon resonance, transcriptome analysis, xenograft mouse model Proceedings of the National Academy of Sciences of the United States of America High 29976840
2018 SALL4 binds the promoter of miR-146a-5p and directly controls its expression in HCC exosomes; this SALL4/miR-146a-5p axis drives M2 macrophage polarization and T cell exhaustion. ChIP assay (SALL4 binding to miR-146a-5p promoter), luciferase reporter, siRNA knockdown, in vivo DEN/CCL4 HCC mouse model Oncoimmunology Medium 31143524
2019 SALL4 binds approximately 50% of mitochondrial genes by ChIP-seq and activates their transcription; SALL4-high cancer cells exhibit increased oxidative phosphorylation, oxygen consumption rate, and mitochondrial membrane potential compared to SALL4-knockdown cells, identifying SALL4 as a transcriptional activator of oxidative phosphorylation genes. ChIP-seq, RNA-seq, oxygen consumption rate measurement, mitochondrial membrane potential assay, xenograft models Gastroenterology High 31446059
2019 Sall4 promotes WNT/β-catenin signaling to maintain neuromesodermal progenitors (NMPs) and regulate their differentiation balance toward neural versus mesodermal fates during body elongation; RNA-seq and ChIP-seq in post-gastrulation embryos confirmed Sall4 directly regulates mesodermal and neural developmental genes. Conditional knockout (TCre), RNA-seq, ChIP-seq, genetic interaction with WNT pathway Development (Cambridge, England) High 31235634
2019 SALL4 directly binds and transcriptionally activates CTNNB1 (β-catenin) promoter (confirmed by ChIP and dual-luciferase assay), activating Wnt/β-catenin signaling and increasing c-Myc and cyclin D1 in cervical cancer cells. ChIP assay, dual-luciferase reporter assay, Western blot, TOP/FOP-Flash Wnt reporter Cancer science Medium 31336010
2020 Thalidomide and IMiD analogs (lenalidomide, pomalidomide) induce SALL4 degradation through the CRBN-containing CRL4 E3 ubiquitin ligase complex; CRBN V388I or SALL4 G416A mutations block IMiD-induced SALL4 degradation and protect hiPSC mesendoderm differentiation from thalidomide, establishing CRBN-dependent SALL4 degradation as the mechanism of teratogenicity. hiPSC differentiation assays, CRBN and SALL4 point-mutant knock-in cells, proteasome inhibitor experiments, flow cytometry Scientific reports High 32071327
2021 SALL4 contains an AT-rich DNA-binding zinc-finger cluster that is essential for genome occupancy; mutation of this AT-binding domain drastically reduces SALL4 chromatin binding, causes premature upregulation of AT-rich neural genes proportional to AT content, and mimics Sall4 null defects including precocious ESC differentiation and embryonic lethality in mice. Zinc-finger mutagenesis, ChIP-seq, RNA-seq, mouse knock-in genetics Molecular cell High 33406384
2021 SALL4 negatively regulates melanoma cell invasiveness through interaction with HDAC2; SALL4 and HDAC2 co-bind a set of invasiveness genes, and SALL4 loss promotes an invasive phenotype; HDAC inhibition phenocopies SALL4 loss, while inhibition of histone acetylation partially reverts the invasiveness induced by SALL4 knockdown. Co-immunoprecipitation (SALL4-HDAC2), ChIP, transcriptional profiling, mouse melanoma model (Tyr::NrasQ61K;Cdkn2a-/-), in vitro invasion assays Nature communications High 34417458
2023 The NuRD complex participates in chromatin closing during early somatic reprogramming; Sall4 uniquely recruits endogenous NuRD components among the reprogramming factors, and disrupting the N-terminal NuRD-interacting motif of Sall4 (by mutation or deletion) abolishes reprogramming ability; grafting this motif onto Jdp2 partially rescues reprogramming, demonstrating that Sall4-NuRD interaction is functionally essential for closing open chromatin. Co-immunoprecipitation, N-terminal motif mutagenesis/deletion, ATAC-seq (chromatin accessibility dynamics), iPSC reprogramming efficiency assays Nature communications High 37208322
2011 SALL4 binds the promoter of ABCA3 (confirmed by ChIP and EMSA) and directly activates ABCA3 expression, while regulating ABCG2 indirectly; SALL4 expression is enriched in drug-resistant side population (SP) cancer cells and its knockdown reduces SP cell frequency, linking SALL4 to drug resistance via ABC transporter regulation. ChIP, EMSA, qRT-PCR, siRNA knockdown, SP cell sorting PloS one Medium 21526180
2015 SALL4 directly binds the c-Myc promoter (confirmed by ChIP) and upregulates c-Myc expression; c-Myc depletion abolishes SALL4-induced EMT (downregulation of E-cadherin, upregulation of N-cadherin) and drug resistance (via ABCB1) in endometrial cancer cells. ChIP assay, siRNA knockdown, Western blot, invasion assays PloS one Medium 26407074
2016 SALL4 directly binds the CD44 promoter (confirmed by ChIP and luciferase assay) and transcriptionally activates CD44; CD44 overexpression rescues SALL4 knockdown-mediated inhibition of gastric cancer cell proliferation and invasion, establishing CD44 as a direct SALL4 target. ChIP, luciferase reporter assay, shRNA knockdown with rescue overexpression, in vivo xenograft Oncogenesis Medium 27819668
2018 SALL4 directly activates TGF-β1 transcription by binding its promoter (confirmed by ChIP and luciferase assay); TGF-β1 knockdown reverses SALL4-mediated promotion of gastric cancer motility and invasion, placing SALL4 upstream of TGF-β/SMAD-driven EMT. ChIP, luciferase reporter assay, microarray for target identification, invasion assays, peritoneal metastasis model Cancer management and research Medium 30349378

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nature cell biology 459 16980957
2006 Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. The Journal of biological chemistry 234 16840789
2013 Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. The New England journal of medicine 205 23758232
2008 Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages. Cell stem cell 189 18804426
2008 Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America 173 19060217
2009 SALL4 is a novel diagnostic marker for testicular germ cell tumors. The American journal of surgical pathology 170 19390421
2013 Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers. Hepatology (Baltimore, Md.) 160 23175232
2006 Murine inner cell mass-derived lineages depend on Sall4 function. Proceedings of the National Academy of Sciences of the United States of America 155 17060609
2019 SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC. Oncoimmunology 154 31143524
2010 Differential roles of Sall4 isoforms in embryonic stem cell pluripotency. Molecular and cellular biology 145 20837710
2012 Functional antagonism between Sall4 and Plzf defines germline progenitors. Cell stem cell 143 22385656
2009 Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. PloS one 143 19440552
2009 SALL4 is a novel sensitive and specific marker for metastatic germ cell tumors, with particular utility in detection of metastatic yolk sac tumors. Cancer 129 19365862
2010 A novel SALL4/OCT4 transcriptional feedback network for pluripotency of embryonic stem cells. PloS one 128 20505821
2009 Roles of Sall4 in the generation of pluripotent stem cells from blastocysts and fibroblasts. Genes to cells : devoted to molecular & cellular mechanisms 126 19476507
2008 SALL4 is a key regulator of survival and apoptosis in human leukemic cells. Blood 125 18487508
2003 Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. Journal of medical genetics 125 12843316
2015 MicroRNA-33b Inhibits Breast Cancer Metastasis by Targeting HMGA2, SALL4 and Twist1. Scientific reports 124 25919570
2013 The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma. Journal of hepatology 121 24012616
2013 SALL4, a novel marker for human gastric carcinogenesis and metastasis. Oncogene 104 24276240
2016 SALL4, the missing link between stem cells, development and cancer. Gene 97 26892498
2018 Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion. Nature communications 89 29593314
2013 SALL4 expression in gonocytes and spermatogonial clones of postnatal mouse testes. PloS one 87 23326552
2016 The regulatory repertoire of PLZF and SALL4 in undifferentiated spermatogonia. Development (Cambridge, England) 82 27068105
2014 SALL4: an emerging cancer biomarker and target. Cancer letters 80 25444934
2016 Inhibition of SALL4 reduces tumorigenicity involving epithelial-mesenchymal transition via Wnt/β-catenin pathway in esophageal squamous cell carcinoma. Journal of experimental & clinical cancer research : CR 76 27329034
2018 SALL4 activates TGF-β/SMAD signaling pathway to induce EMT and promote gastric cancer metastasis. Cancer management and research 74 30349378
2011 SALL4 is essential for cancer cell proliferation and is overexpressed at early clinical stages in breast cancer. International journal of oncology 74 21274508
2013 Role of SALL4 in the progression and metastasis of colorectal cancer. Journal of biomedical science 73 23363002
2011 Overexpression of SALL4 in lung cancer and its importance in cell proliferation. Oncology reports 71 21725617
2006 SALL4 is directly activated by TCF/LEF in the canonical Wnt signaling pathway. Biochemical and biophysical research communications 66 16899215
2013 Low-expression of microRNA-107 inhibits cell apoptosis in glioma by upregulation of SALL4. The international journal of biochemistry & cell biology 62 23811124
2007 A Sall4 mutant mouse model useful for studying the role of Sall4 in early embryonic development and organogenesis. Genesis (New York, N.Y. : 2000) 62 17216607
2016 Sall4 controls differentiation of pluripotent cells independently of the Nucleosome Remodelling and Deacetylation (NuRD) complex. Development (Cambridge, England) 60 27471257
2009 Diagnostic utility of SALL4 in primary germ cell tumors of the central nervous system: a study of 77 cases. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 59 19820689
2013 Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex. Blood 58 23287862
2011 SALL4, a stem cell factor, affects the side population by regulation of the ATP-binding cassette drug transport genes. PloS one 57 21526180
2013 An Oct4-Sall4-Nanog network controls developmental progression in the pre-implantation mouse embryo. Molecular systems biology 56 23295861
2017 Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes. Stem cell reports 55 28867346
2015 SALL4 as an Epithelial-Mesenchymal Transition and Drug Resistance Inducer through the Regulation of c-Myc in Endometrial Cancer. PloS one 55 26407074
2008 Sall1, sall2, and sall4 are required for neural tube closure in mice. The American journal of pathology 54 18818376
2019 New High-Throughput Screening Identifies Compounds That Reduce Viability Specifically in Liver Cancer Cells That Express High Levels of SALL4 by Inhibiting Oxidative Phosphorylation. Gastroenterology 53 31446059
2016 MicroRNA-98 acts as a tumor suppressor in hepatocellular carcinoma via targeting SALL4. Oncotarget 53 27677076
2006 sall4 acts downstream of tbx5 and is required for pectoral fin outgrowth. Development (Cambridge, England) 52 16501170
2011 Enhanced self-renewal of hematopoietic stem/progenitor cells mediated by the stem cell gene Sall4. Journal of hematology & oncology 51 21943195
2018 Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide. Proceedings of the National Academy of Sciences of the United States of America 49 29976840
2019 SALL4 promotes the tumorigenicity of cervical cancer cells through activation of the Wnt/β-catenin pathway via CTNNB1. Cancer science 47 31336010
2015 miR-219-5p plays a tumor suppressive role in colon cancer by targeting oncogene Sall4. Oncology reports 47 26238082
2021 Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4. Cell death discovery 45 34455417
2016 SALL4 expression in gestational trophoblastic tumors: a useful tool to distinguish choriocarcinoma from placental site trophoblastic tumor and epithelioid trophoblastic tumor. Human pathology 45 27068524
2019 Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Jdp2-Jhdm1b-Mkk6-Glis1-Nanog-Essrb-Sall4. Cell reports 43 31216469
2015 Stemness factor Sall4 is required for DNA damage response in embryonic stem cells. The Journal of cell biology 43 25733712
2014 ERG and SALL4 expressions in SMARCB1/INI1-deficient tumors: a useful tool for distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Human pathology 43 25479928
2018 miR-103/miR-195/miR-15b Regulate SALL4 and Inhibit Proliferation and Migration in Glioma. Molecules (Basel, Switzerland) 42 30423818
2011 Dedifferentiation and the role of sall4 in reprogramming and patterning during amphibian limb regeneration. Developmental dynamics : an official publication of the American Association of Anatomists 42 21305648
2013 A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis. The Journal of clinical investigation 41 24051379
2022 SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance. International journal of molecular sciences 40 35216168
2012 Stemness-related factor Sall4 interacts with transcription factors Oct-3/4 and Sox2 and occupies Oct-Sox elements in mouse embryonic stem cells. The Journal of biological chemistry 39 23269686
2019 SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway. Cancer medicine 37 30907073
2016 SALL4 promotes gastric cancer progression through activating CD44 expression. Oncogenesis 37 27819668
2018 SALL4 as a transcriptional and epigenetic regulator in normal and leukemic hematopoiesis. Biomarker research 36 29308206
2021 SALL4 controls cell fate in response to DNA base composition. Molecular cell 33 33406384
2016 Anticancer Properties of Chrysin on Colon Cancer Cells, In vitro and In vivo with Modulation of Caspase-3, -9, Bax and Sall4. Iranian journal of biotechnology 33 28959334
2020 miR-296-5p suppresses stem cell potency of hepatocellular carcinoma cells via regulating Brg1/Sall4 axis. Cellular signalling 32 32320856
2017 SALL4 promotes glycolysis and chromatin remodeling via modulating HP1α-Glut1 pathway. Oncogene 32 28759035
2013 Tyrosinekinase inhibition facilitates cooperation of transcription factor SALL4 and ABC transporter A3 towards intrinsic CML cell drug resistance. British journal of haematology 32 23432194
2018 Upregulation of SALL4 by EGFR activation regulates the stemness of CD44-positive lung cancer. Oncogenesis 31 29691367
2017 The stem cell factor SALL4 is an essential transcriptional regulator in mixed lineage leukemia-rearranged leukemogenesis. Journal of hematology & oncology 31 28974232
2015 Significance of SALL4 as a drug‑resistant factor in lung cancer. International journal of oncology 31 25646965
2019 Sall4 regulates neuromesodermal progenitors and their descendants during body elongation in mouse embryos. Development (Cambridge, England) 30 31235634
2015 Sall4 is essential for mouse primordial germ cell specification by suppressing somatic cell program genes. Stem cells (Dayton, Ohio) 30 25263278
2012 Sumoylation is important for stability, subcellular localization, and transcriptional activity of SALL4, an essential stem cell transcription factor. The Journal of biological chemistry 30 23012367
2013 A Cdx4-Sall4 regulatory module controls the transition from mesoderm formation to embryonic hematopoiesis. Stem cell reports 29 24286030
2023 The NuRD complex cooperates with SALL4 to orchestrate reprogramming. Nature communications 28 37208322
2020 Thalidomide Inhibits Human iPSC Mesendoderm Differentiation by Modulating CRBN-dependent Degradation of SALL4. Scientific reports 28 32071327
2009 Overexpression of the novel oncogene SALL4 and activation of the Wnt/beta-catenin pathway in myelodysplastic syndromes. Cancer genetics and cytogenetics 28 19781444
2022 SALL4: An Intriguing Therapeutic Target in Cancer Treatment. Cells 27 36010677
2011 The role of stem cell factor SALL4 in leukemogenesis. Critical reviews in oncogenesis 27 22150312
2021 Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4. Nature communications 26 34417458
2011 Immunoexpression of SALL4 in Wilms tumors and developing kidney. Pathology oncology research : POR 26 21258884
2018 miR-16 targets SALL4 to repress the proliferation and migration of gastric cancer. Oncology letters 25 30127890
2019 Whole-exome sequencing reveals SALL4 variants in premature ovarian insufficiency: an update on genotype-phenotype correlations. Human genetics 24 30603774
2016 Knockdown of SALL4 inhibits the proliferation and reverses the resistance of MCF-7/ADR cells to doxorubicin hydrochloride. BMC molecular biology 24 26935744
2016 Knockdown of Sall4 inhibits intrahepatic cholangiocarcinoma cell migration and invasion in ICC-9810 cells. OncoTargets and therapy 24 27601921
2020 An IMiD-induced SALL4 degron system for selective degradation of target proteins. Communications biology 23 32948804
2014 Differential SALL4 immunoexpression in malignant rhabdoid tumours and epithelioid sarcomas. Histopathology 23 24827994
2008 Sall4 isoforms act during proximal-distal and anterior-posterior axis formation in the mouse embryo. Genesis (New York, N.Y. : 2000) 23 18781635
2015 Inhibition of SALL4 suppresses carcinogenesis of colorectal cancer via regulating Gli1 expression. International journal of clinical and experimental pathology 22 26617716
2021 Up-Regulation of SALL4 Is Associated With Survival and Progression via Putative WNT Pathway in Gastric Cancer. Frontiers in cell and developmental biology 21 33644042
2019 miR-188-5p emerges as an oncomiRNA to promote gastric cancer cell proliferation and migration via upregulation of SALL4. Journal of cellular biochemistry 21 31009138
2012 Diagnostic utility of CD117, CD133, SALL4, OCT4, TCL1 and glypican-3 in malignant germ cell tumors of the ovary. The journal of obstetrics and gynaecology research 21 22448662
2012 Aberrant hypomethylation of SALL4 gene in patients with myelodysplastic syndrome. Leukemia research 21 23122807
2021 miR-497-5p/SALL4 axis promotes stemness phenotype of choriocarcinoma and forms a feedback loop with DNMT-mediated epigenetic regulation. Cell death & disease 20 34732693
2016 SOX1 is correlated to stemness state regulator SALL4 through progression and invasiveness of esophageal squamous cell carcinoma. Gene 20 27576349
2021 Targeting an Inducible SALL4-Mediated Cancer Vulnerability with Sequential Therapy. Cancer research 19 34593523
2012 Aberrant hypomethylation of SALL4 gene is associated with intermediate and poor karyotypes in acute myeloid leukemia. Clinical biochemistry 19 23201546
2021 Long noncoding HOXA11-AS knockdown suppresses the progression of non-small cell lung cancer by regulating miR-3619-5p/SALL4 axis. Journal of molecular histology 17 34050851
2023 The new advance of SALL4 in cancer: Function, regulation, and implication. Journal of clinical laboratory analysis 16 37337914
2014 SALL4: engine of cell stemness. Current gene therapy 16 25174577
2012 Role of SALL4 in hematopoiesis. Current opinion in hematology 16 22555391