Affinage

SALL4

Sal-like protein 4 · UniProt Q9UJQ4

Length
1053 aa
Mass
112.2 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SALL4 is a zinc-finger transcription factor that governs stem-cell identity and cell-fate transitions by binding AT-rich genomic enhancers through a specific zinc-finger cluster whose inactivation phenocopies the full Sall4-null state, including embryonic lethality and precocious neural differentiation (PMID:33406384). In embryonic and extraembryonic stem cells SALL4 operates within an interconnected autoregulatory transcriptional network—physically associating with NANOG and co-occupying shared enhancers (PMID:16840789), directly activating Oct4/Pou5f1 (PMID:16980957), and engaging distinct circuits (Oct4/Sox2/Nanog versus Gata4/6/Sox7/17) depending on lineage context (PMID:18804426)—and is cell-autonomously required for epiblast and primitive endoderm formation from the inner cell mass (PMID:17060609). SALL4 functions both as a transcriptional activator and as a repressor: its N-terminal motif recruits the Mi-2/NuRD nucleosome-remodeling and deacetylase complex to close chromatin and silence tumor-suppressor loci such as PTEN and SALL1 (PMID:19440552, PMID:37208322), and disruption of this SALL4–NuRD interface by a structurally-defined peptide releases PTEN repression, converts SALL4 to a singular activator, and blocks tumor growth (PMID:23758232, PMID:29976840). SALL4 additionally couples to DNA methyltransferases (PMID:22128185) and to a panel of chromatin modifiers including MLL, DOT1L, LSD1/KDM1A and HDAC2 to set H3K4me3, H3K79me2/3 and acetylation marks at target promoters in leukemic and other contexts (PMID:24051379, PMID:25737450, PMID:28974232, PMID:34417458). In germ-cell and progenitor systems SALL4 antagonizes PLZF to balance self-renewal against differentiation (PMID:22385656) and suppresses somatic-program genes (PMID:25263278), and it sustains WNT/β-catenin-driven neuromesodermal progenitors during body elongation (PMID:31235634). Germline loss models limb and heart malformation consistent with Okihiro/Holt-Oram syndromes through a Tbx5–Sall4 feed-forward circuit (PMID:16380715). Across cancers SALL4 drives oncogenic transcriptional programs—activating c-Myc, CD44, VEGF and glycolytic genes—and shapes the tumor immune microenvironment, with HBV/STAT3 signaling driving its re-expression in hepatocellular carcinoma (PMID:29593314, PMID:27797380).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2005 High

    Established SALL4 as a developmentally regulated patterning gene whose dosage controls limb and heart morphogenesis, anchoring its physiological relevance to human malformation syndromes.

    Evidence Mouse gene-trap genetics with epistasis against Tbx5 and phenotypic analysis

    PMID:16380715

    Open questions at the time
    • Direct SALL4 target genes mediating limb/heart patterning not defined
    • Molecular nature of the Tbx5–Sall4 feed-forward circuit unresolved
  2. 2006 High

    Placed SALL4 at the top of the pluripotency network by showing it directly activates Oct4 and physically partners with NANOG in a positive autoregulatory loop, answering how SALL4 enforces stem-cell identity.

    Evidence ChIP, reporter assays, in vivo zygote siRNA, affinity-MS, reciprocal Co-IP and GST pulldown in ES cells

    PMID:16840789 PMID:16980957

    Open questions at the time
    • Did not define the DNA motif SALL4 recognizes
    • Mechanism of transactivation domain not mapped
  3. 2006 Medium

    Identified an upstream input by linking canonical Wnt/TCF-LEF signaling to SALL4 promoter activation, beginning to explain how SALL4 expression is set.

    Evidence SALL4 promoter reporter assays with TCF/LEF site mutagenesis and LEF1/TCF4E transfection

    PMID:16899215

    Open questions at the time
    • No in vivo ChIP confirmation of TCF/LEF occupancy
    • Reporter-based, single lab
  4. 2007 High

    Connected SALL4 to self-renewal effectors and to activating chromatin marks by showing it activates Bmi-1 alongside elevated H3K4me3/H3K79me2, revealing an epigenetic activation mode.

    Evidence Reporter assays, ChIP in myeloid stem cells, siRNA, transgenic and knockout mice

    PMID:17557835

    Open questions at the time
    • Histone methyltransferases responsible not yet identified
    • Mechanism coupling SALL4 binding to mark deposition unknown
  5. 2008 High

    Demonstrated cell-autonomous requirement and lineage-specific rewiring, showing SALL4 drives both embryonic and extraembryonic endoderm circuits using distinct target sets.

    Evidence Conditional knockout blastocyst culture, chimera analysis, genome-wide ChIP-chip and siRNA in ESC and XEN cells

    PMID:17060609 PMID:18804426

    Open questions at the time
    • How SALL4 selects context-specific targets not explained
    • Cofactors switching ESC vs XEN programs unidentified
  6. 2009 High

    Defined SALL4's repressive arm by showing it associates with the HDAC-bearing NuRD complex and co-occupies PTEN/SALL1 promoters, establishing SALL4 as a recruiter of corepressor machinery.

    Evidence Tandem MS of immunocomplexes, Co-IP, HDAC activity assay, ChIP, transgenic mouse

    PMID:19440552

    Open questions at the time
    • Fraction of SALL4 bound to NuRD versus free not quantified
    • Whether SALL4 recruits NuRD to chromatin not directly tested
  7. 2011 High

    Extended the repression mechanism to DNA methylation, showing SALL4 binds DNMT1/3A/3B and increases CpG methylation at silenced targets such as PTEN.

    Evidence Co-IP, DNMT enzyme activity assay, ChIP, bisulfite sequencing, VPA/5-azaC inhibitors

    PMID:22128185

    Open questions at the time
    • Direct recruitment of DNMTs to specific loci not resolved at genome scale
    • Interplay between NuRD and DNMT repression not dissected
  8. 2012 High

    Revealed a competitive chromatin-partitioning mechanism with PLZF that sets the self-renewal/differentiation switch in spermatogonial progenitors.

    Evidence Co-IP, ChIP, genetic knockout/overexpression and Kit/Sall1 readouts in SPCs

    PMID:22385656

    Open questions at the time
    • Structural basis of mutual chromatin displacement unknown
    • Generality beyond germline progenitors untested at this stage
  9. 2013 High

    Validated SALL4–NuRD repression as a druggable oncogenic dependency by showing peptide disruption releases PTEN and inhibits hepatocellular carcinoma tumorigenesis.

    Evidence RNAi loss-of-function, xenografts, N-terminal peptide blockade, expression analysis

    PMID:23758232

    Open questions at the time
    • Peptide pharmacology and delivery not characterized
    • Whether activator functions persist after disruption not yet shown
  10. 2013 High

    Built the SALL4/MLL/HOXA9 leukemogenic axis, showing SALL4 binds HOXA9, partners with MLL, and deposits activating marks to drive myeloid leukemia.

    Evidence ChIP, reciprocal Co-IP, siRNA, replating and in vivo AML transplantation

    PMID:24051379

    Open questions at the time
    • Direct enzymatic basis of mark deposition not isolated
    • Relationship to NuRD repression at the same cells unclear
  11. 2013 Medium

    Expanded SALL4's oncogenic activator targets to c-Myc and to adhesion/EMT regulators (CDH1/ZEB1), broadening its pro-tumor transcriptional program.

    Evidence ChIP, gain/loss-of-function, xenograft (c-Myc); shRNA/overexpression with motility assays (CDH1/ZEB1)

    PMID:23954296 PMID:24336327

    Open questions at the time
    • No direct ChIP at CDH1/ZEB1 promoters
    • Single-lab target validations
  12. 2015 High

    Linked SALL4 to histone demethylase recruitment, showing SALL4 binds RARα and recruits LSD1/KDM1A to block ATRA-induced differentiation in AML.

    Evidence Co-IP for RARα and LSD1, ChIP for histone methylation, knockdown, flow cytometry differentiation

    PMID:25737450

    Open questions at the time
    • Direct LSD1 catalytic contribution at SALL4 targets not isolated
    • Generality across leukemia subtypes untested here
  13. 2016 High

    Challenged the obligate SALL4–NuRD recruitment model by showing SALL4 is dispensable for ES-cell pluripotency and instead acts as an enhancer-binding restraint on neural genes, with much SALL4 acting independently of NuRD.

    Evidence Conditional ESC knockout, ChIP-seq, quantitative MS of NuRD interaction, RNA-seq, differentiation assays

    PMID:27471257

    Open questions at the time
    • Reconciliation with NuRD-recruitment claims context-dependent and unresolved
    • How free SALL4 represses transcription mechanistically unclear
  14. 2016 High

    Established SALL4's roles in germline and maternal epigenetic programming, including oocyte maturation and intron-biased spermatogonial binding distinct from PLZF.

    Evidence Maternal CRISPR knockout with DNA-methylation/histone profiling; spermatogonial ChIP-seq with motif analysis and knockdown

    PMID:27068105 PMID:28031467

    Open questions at the time
    • Direct demethylase targets driving oocyte phenotype not pinpointed
    • Functional meaning of intronic SALL4 binding unresolved
  15. 2017 High

    Consolidated SALL4 as a chromatin-modifier hub in spermatogonia and leukemia, repressing Foxl1/Dusp4 via NuRD and co-occupying MLL-AF9 targets with DOT1L/LSD1, with leukemia-selective dependency.

    Evidence Inducible knockouts, Co-IP (NuRD, DOT1L, LSD1), ChIP/ChIP-seq, apoptosis/cell-cycle and in vivo transplantation

    PMID:28867346 PMID:28974232

    Open questions at the time
    • Which modifier interaction dominates at a given locus unclear
    • Selectivity for malignant over normal cells mechanistically undefined
  16. 2018 High

    Resolved the atomic basis of SALL4–NuRD binding and delivered a high-affinity disruptor peptide that reprograms SALL4 to an activator and shrinks tumors, converting the corepressor interface into a therapeutic target.

    Evidence X-ray crystallography of SALL4(1–12)–RBBP4, peptide engineering, transcriptome profiling, xenograft

    PMID:29976840

    Open questions at the time
    • In vivo deliverability/pharmacokinetics of FFW peptide not established
    • Off-target effects on other RBBP4 partners not assessed
  17. 2018 Medium

    Identified SALL4 as a regulator of the tumor immune microenvironment, showing HBV/STAT3-driven SALL4 represses miR-200c to de-repress PD-L1 and promote T-cell exhaustion in HCC.

    Evidence ChIP, miR-200c 3'-UTR reporter, pathway over/knockdown, T-cell exhaustion assays, clinical correlation

    PMID:29593314

    Open questions at the time
    • Single-lab axis
    • In vivo causality of each node not fully separated
  18. 2018 Medium

    Connected SALL4 to metastatic and stemness programs in solid tumors through direct activation of TGF-β1 and a KHDRBS3–CD44 splicing axis.

    Evidence ChIP/reporter and TGF-β1 rescue (gastric); shRNA/overexpression with splicing isoform analysis (breast)

    PMID:29356399 PMID:30349378

    Open questions at the time
    • No direct ChIP at KHDRBS3 promoter
    • Single-lab, context-specific findings
  19. 2019 High

    Showed SALL4 sustains WNT/β-catenin-dependent neuromesodermal progenitors to control mesoderm-versus-neural fate during body elongation, integrating its developmental and signaling roles.

    Evidence Conditional TCre knockout, RNA-seq, SALL4 ChIP-seq, WNT reporters, embryonic phenotyping

    PMID:31235634

    Open questions at the time
    • Direct WNT-pathway target of SALL4 not pinpointed
    • Mechanism of fate-balance control downstream of SALL4 unclear
  20. 2020 Medium

    Linked SALL4 to metabolic reprogramming by showing direct activation of glycolytic genes (HK-2) and feedback control of its own expression via the Brg1/miR-296-5p axis.

    Evidence ChIP/reporter with glycolysis assays and HK-2 rescue; Brg1 ChIP at SALL4 promoter with miRNA manipulation

    PMID:32320856 PMID:32489324

    Open questions at the time
    • Single-lab axes
    • Direct versus indirect metabolic control not fully separated
  21. 2021 High

    Pinpointed the AT-rich binding zinc-finger cluster as the essential determinant of SALL4 genome occupancy and developmental function, and revealed a context where SALL4 restrains invasiveness via HDAC2.

    Evidence Genome-wide AT-binding screen, domain-specific mutagenesis with embryonic lethality, ChIP-seq/RNA-seq; melanoma KO with HDAC2 co-binding ChIP and HDAC-inhibitor epistasis

    PMID:33406384 PMID:34417458

    Open questions at the time
    • Structural basis of AT recognition not solved
    • How AT-content sensing selects which genes stay silenced unresolved
  22. 2023 High

    Defined SALL4 as the indispensable NuRD-recruiting factor for chromatin closing during reprogramming and extended its activator role to angiogenic VEGF genes in cancer.

    Evidence ATAC-seq, Co-IP, N-terminal motif deletion and motif-grafting rescue in iPSC reprogramming; ChIP/EMSA/reporter and HUVEC assays for VEGF

    PMID:37208322 PMID:37525212

    Open questions at the time
    • Reconciliation of recruiting-NuRD vs NuRD-independent models across systems incomplete
    • VEGF axis single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SALL4 toggles between NuRD-dependent repression and direct activation at individual loci, and the rules by which AT-rich enhancer binding is translated into context-specific gene programs, remain unresolved.
  • No unified model reconciling NuRD-recruiting (37208322) and NuRD-independent (27471257) data
  • Genome-scale determinants of activation versus repression undefined
  • No structure of the AT-binding zinc-finger cluster on DNA

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-1643685 Disease 6 R-HSA-4839726 Chromatin organization 6 R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3
Partners
DOT1LHDAC2LSD1/KDM1AMLLNANOGPLZFRARARBBP4
Complex memberships
Mi-2/NuRD

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SALL4 binds to the highly conserved distal enhancer region of the Pou5f1 (Oct4) gene and transcriptionally activates Pou5f1 expression in vivo and in vitro; siRNA knockdown of Sall4 in mouse zygotes reduced both Sall4 and Oct4 mRNAs and expanded Cdx2 expression into the inner cell mass, establishing SALL4 as a direct transcriptional activator of Oct4. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA microinjection into mouse zygotes, in vitro transcription assays Nature cell biology High 16980957
2006 SALL4 physically interacts with NANOG in embryonic stem cells (identified by affinity purification/MS, confirmed by Co-IP and GST pulldown); SALL4 and NANOG co-occupy each other's enhancer regions and many shared genomic loci, forming a positive autoregulatory circuit that maintains ES cell-specific enhancer activity. Affinity purification coupled to LC-MS/MS, co-immunoprecipitation, GST pulldown, chromatin immunoprecipitation (ChIP), RNAi knockdown with luciferase enhancer activity assays The Journal of biological chemistry High 16840789
2009 SALL4 associates with the Mi-2/NuRD (Nucleosome Remodeling and Deacetylase) complex, identified by tandem mass spectrometry of SALL4 immunocomplexes; this complex carries HDAC activity. SALL4 directly represses PTEN and SALL1 transcription through co-occupancy of their promoters with NuRD components, as confirmed by ChIP. Tandem mass spectrometry of SALL4 immunocomplexes, co-immunoprecipitation, HDAC activity assay, ChIP, qRT-PCR, SALL4 transgenic mouse model PloS one High 19440552
2007 SALL4 directly binds the Bmi-1 promoter and transcriptionally activates Bmi-1 expression in a dose-dependent manner; SALL4-bound Bmi-1 promoter regions show elevated H3-K4 trimethylation and H3-K79 dimethylation, providing an epigenetic mechanism for SALL4-mediated Bmi-1 upregulation. Luciferase reporter assay with promoter deletion constructs, ChIP from myeloid stem cells, siRNA knockdown in HL-60 cells, SALL4 transgenic mice, gene targeting (heterozygous deletion) Proceedings of the National Academy of Sciences of the United States of America High 17557835
2011 SALL4 represses gene expression through direct interaction with DNA methyltransferases (DNMT1, DNMT3A, DNMT3B); co-IP and DNMT enzyme activity assays confirmed physical interaction; SALL4 isoforms co-occupy their own promoter with DNMTs, and SALL4 overexpression increases CpG island methylation of silenced target genes (including PTEN). HDAC inhibition and DNA methylation inhibition synergistically block SALL4-mediated repression. Co-immunoprecipitation, DNMT enzymatic activity assay, ChIP, luciferase reporter assay, bisulfite sequencing/CpG methylation analysis, pharmacological inhibitors (VPA, 5-azaC) The Journal of biological chemistry High 22128185
2013 Blocking SALL4–NuRD corepressor interactions (using a peptide targeting SALL4's N-terminal region) releases repression of PTEN and inhibits tumor formation in xenograft models; SALL4 loss-of-function studies confirmed its critical role in hepatocellular carcinoma cell survival and tumorigenicity. Loss-of-function (RNAi), in vivo xenograft assays, peptide inhibitor blocking SALL4–NuRD interaction, gene expression analysis The New England journal of medicine High 23758232
2018 Crystal structure of SALL4 N-terminal peptide (residues 1–12) complexed with RBBp4 (NuRD chaperone subunit) resolved at 2.7 Å; a therapeutic peptide (FFW) designed from this structure disrupts the SALL4–NuRD interaction with 23 nM affinity, converting SALL4 from a dual repressor-activator to a singular activator mode and inhibiting xenograft tumor growth by 85%. X-ray crystallography, peptide design with systematic truncation/substitution, transcriptome profiling, in vivo xenograft tumor model Proceedings of the National Academy of Sciences of the United States of America High 29976840
2013 SALL4 directly binds to the HOXA9 promoter in leukemic cells; SALL4 overexpression increases activating histone marks (H3-K4me3, H3-K79me2) at the HOXA9 promoter; SALL4 physically interacts with MLL and co-occupies the HOXA9 promoter with MLL, defining a SALL4/MLL/HOXA9 pathway in myeloid leukemogenesis. ChIP, co-immunoprecipitation (SALL4–MLL interaction), siRNA knockdown, in vitro replating assay, in vivo AML transplantation model The Journal of clinical investigation High 24051379
2016 SALL4 is dispensable for mouse ES cell pluripotency maintenance; instead, SALL4 functions as an enhancer-binding protein that prevents precocious activation of the neural gene expression program. Although a proportion of SALL4 protein physically associates with NuRD, SALL4 neither recruits NuRD to chromatin nor regulates transcription via NuRD; free SALL4 protein regulates transcription independently of NuRD. Conditional Sall4 knockout in ES cells, genome-wide enhancer binding (ChIP-seq), quantitative proteomics (MS) of NuRD interaction, transcriptome analysis (RNA-seq), differentiation assays Development (Cambridge, England) High 27471257
2021 SALL4 binds AT-rich genomic motifs via a specific zinc-finger cluster; mutation of this AT-binding domain drastically reduces SALL4 genome occupancy and prematurely upregulates genes in proportion to their AT content, causing precocious neural differentiation. This AT-binding zinc-finger cluster is functionally essential, as its inactivation mimics full Sall4 null phenotypes including embryonic lethality; deletion of two other zinc-finger clusters was phenotypically neutral. Genome-wide screen for AT-binding proteins, domain-specific mutagenesis, ChIP-seq, RNA-seq, mouse knockout (domain-specific), embryonic lethality assessment Molecular cell High 33406384
2006 SALL4 is directly activated by TCF/LEF transcription factors in the canonical Wnt signaling pathway; a consensus TCF/LEF-binding site within a 31 bp minimal SALL4 promoter region is required, as mutation of this site reduces promoter activation by LEF1 and TCF4E. SALL4 promoter cloning, luciferase reporter assay, site-directed mutagenesis of TCF/LEF binding site, transient transfection with LEF1 and TCF4E Biochemical and biophysical research communications Medium 16899215
2005 Tbx5 regulates Sall4 expression in developing mouse forelimb and heart; Tbx5 and Sall4 interact both positively and negatively in a feed-forward circuit to regulate anterior forelimb and heart patterning; Sall4 heterozygous gene-trap mice exhibit limb and heart defects modeling human Okihiro/Holt-Oram syndromes. Mouse genetics (Sall4 gene-trap heterozygous), in situ hybridization, compound mutant analysis (epistasis), expression analysis in Tbx5 mutants Nature genetics High 16380715
2012 In differentiating spermatogonial progenitor cells (SPCs), SALL4 physically interacts with PLZF; SALL4 sequesters PLZF to non-cognate chromatin domains to derepress Kit expression (a PLZF-repressed differentiation target); conversely, PLZF displaces SALL4 from cognate chromatin to induce Sall1 expression, creating a mutual antagonism that defines the self-renewal vs. differentiation balance. Co-immunoprecipitation (SALL4-PLZF interaction), ChIP, genetic knockout/overexpression in SPCs, Kit expression analysis Cell stem cell High 22385656
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. Trophoblast lineage development is unaffected by Sall4 loss. Conditional mouse knockout (Sall4-null), blastocyst culture and stem cell line derivation, chimera analysis Proceedings of the National Academy of Sciences of the United States of America High 17060609
2008 Sall4 regulates distinct gene sets and transcriptional circuits in embryonic stem cells (ESCs) versus extraembryonic endoderm (XEN) cells; in ESCs, Sall4 forms an interconnected autoregulatory network with Oct4, Sox2, and Nanog; in XEN cells, Sall4 regulates Gata4, Gata6, Sox7, and Sox17. Depletion of Sall4 in XEN cells disrupts self-renewal and induces differentiation. Genome-wide ChIP-chip, siRNA knockdown in both ESC and XEN cells, gene expression profiling, differentiation assays Cell stem cell High 18804426
2016 Maternal SALL4 is required for epigenetic maturation of mouse oocytes; maternal-specific Sall4 deletion (via CRISPR/Cas9) causes oocyte developmental arrest at the germinal vesicle stage with non-surrounded nucleus and prevents meiosis resumption. Loss of maternal Sall4 causes failure of DNA methylation establishment and dysregulation of H3K4me3 and H3K27me3 modifications by altering expression of histone demethylases Kdm5b, Kdm6a, and Kdm6b. Maternal-specific CRISPR/Cas9 knockout, bisulfite sequencing (DNA methylation), ChIP for histone marks, gene expression analysis (qRT-PCR) The Journal of biological chemistry High 28031467
2017 SALL4 associates with the NuRD co-repressor complex in undifferentiated spermatogonia and represses tumor suppressor genes Foxl1 and Dusp4; aberrant Foxl1 activation inhibits undifferentiated cell growth and survival, while DUSP4 suppresses self-renewal pathways. Inducible knockout showed short-term integrity of differentiating spermatogonia requires SALL4, while long-term undifferentiated spermatogonial function and stem cell-driven regeneration also depend on SALL4. Inducible knockout mouse model, Co-IP (SALL4-NuRD), ChIP, gene expression analysis, functional regeneration assays Stem cell reports High 28867346
2015 SALL4 directly associates with retinoic acid receptor α (RARα) and modulates ATRA target gene expression; SALL4 recruits lysine-specific histone demethylase 1 (LSD1/KDM1A) to target genes and alters their histone methylation status, thereby blocking ATRA-induced AML differentiation. Co-inhibition of LSD1 and SALL4 with ATRA produced the strongest anti-AML effect. Co-immunoprecipitation (SALL4-RARα and SALL4-LSD1), ChIP for histone methylation, siRNA knockdown, SALL4 overexpression, flow cytometry differentiation assays The Journal of biological chemistry High 25737450
2017 In MLL-AF9 leukemia, SALL4 physically interacts with DOT1L (H3K79 methyltransferase) and LSD1/KDM1A, co-occupies MLL-AF9 target gene promoters, and regulates H3K79me2/3 and H3K4me3 marks at those promoters. SALL4 loss in MLL-AF9-transformed cells induced apoptosis and G1 cell cycle arrest; normal hematopoiesis is unaffected by Sall4 deletion. ChIP-seq, Co-immunoprecipitation (SALL4-DOT1L, SALL4-LSD1), mRNA microarray, inducible Cre knockout, apoptosis/cell cycle assays, in vivo leukemia transplantation Journal of hematology & oncology High 28974232
2017 SALL4 promotes open chromatin by recruiting ubiquitin E3 ligase CUL4B to HP1α, thereby destabilizing HP1α (heterochromatin protein 1α). This mechanism upregulates Glut1 expression and promotes glycolysis; impaired DNA damage response (DDR) in SALL4-deficient cells can be rescued by restoring Glut1 expression, linking SALL4-HP1α-Glut1 axis to DDR and chemoresistance. Co-immunoprecipitation (SALL4-CUL4B-HP1α), chromatin accessibility assay, glucose uptake/glycolysis assays, rescue experiments with Glut1 Oncogene Medium 28759035
2019 SALL4 binds to the promoter of miR-146a-5p and directly controls its expression in HCC exosomes; the SALL4/miR-146a-5p regulatory axis drives M2 macrophage polarization and T cell exhaustion (via induction of PD-1 and CTLA-4 on T cells). Blocking this axis reduced inhibitory receptor expression on T cells and delayed HCC progression in a mouse model. ChIP (SALL4 binding to miR-146a-5p promoter), exosome isolation and miRNA quantification, macrophage polarization assays, T cell functional assays, in vivo DEN/CCL4-induced HCC mouse model Oncoimmunology Medium 31143524
2018 HBV-induced STAT3 activation drives re-expression of SALL4 in adult hepatocytes; SALL4 then occupies the miR-200c promoter to suppress miR-200c transcription, which in turn de-represses PD-L1 (CD274), promoting T cell exhaustion. The HBV-pSTAT3-SALL4-miR-200c-PD-L1 axis was confirmed by ChIP and miR-200c 3'-UTR reporter assays. ChIP (SALL4 binding to miR-200c promoter), luciferase 3'-UTR reporter assay, overexpression/knockdown of pathway components, T cell exhaustion assays, clinical HCC specimen correlation Nature communications Medium 29593314
2016 DNA demethylation of CpG sites downstream of the SALL4 transcriptional start site enables binding of OCT4 and STAT3 at those sites, recruitment of chromatin remodeling complex BRG1/BAF, and enhanced RNA polymerase II elongation through the SALL4 locus, thereby driving SALL4 re-expression in HBV-related HCC. BRG1 knockdown reduced SALL4 expression, while BRG1 overexpression increased it. Bisulfite sequencing PCR, ChIP (RNA Pol II, OCT4, STAT3, BRG1 occupancy), sequential ChIP (co-occupancy), BRG1 knockdown/overexpression Oncogene Medium 27797380
2015 Sall4 is required for mouse primordial germ cell (PGC) specification; conditional inactivation of Sall4 during PGC specification caused somatic program gene derepression (Hoxa1, Hoxb1) in PGC progenitors without impairing stem cell program activation. Sall4 was shown to bind somatic cell program gene loci (occupied by Prdm1 in embryonic carcinoma cells), and since Sall4 and Prdm1 associate with the HDAC repressor complex, Sall4 likely suppresses the somatic program by recruiting this repressor complex with Prdm1. Conditional Sall4 knockout, qRT-PCR for somatic program genes, ChIP (Sall4 binding at Hoxa1/Hoxb1 loci in differentiated ESCs), apoptosis assays Stem cells (Dayton, Ohio) Medium 25263278
2019 Sall4 promotes WNT/β-catenin signaling to maintain neuromesodermal progenitors (NMPs) and control their differentiation balance toward mesodermal versus neural fates during mouse body elongation; SALL4 ChIP-seq identified direct target genes in both mesodermal and neural compartments; Sall4 deletion caused body/tail truncation due to NMP depletion at the trunk-to-tail transition. Conditional Sall4 knockout (TCre), RNA-seq, SALL4 ChIP-seq, WNT/β-catenin signaling reporters, histological and molecular phenotype analysis Development (Cambridge, England) High 31235634
2016 In undifferentiated spermatogonia, SALL4 preferentially binds gene introns (while PLZF binds gene promoters); SALL4-bound sites contain motifs for the differentiation factor DMRT1. PLZF/SALL4 shared sites predominantly contain only PLZF motifs, indicating non-autonomous binding. Both PLZF- and SALL4-unique target genes involved in SSC self-renewal and differentiation are suppressed following their respective knockdown. ChIP-seq in THY1+ spermatogonia, motif analysis, siRNA knockdown followed by mRNA expression profiling Development (Cambridge, England) High 27068105
2023 During somatic cell reprogramming, the NuRD complex participates in closing open chromatin in an early phase; SALL4 (but not Jdp2, Glis1, or Esrrb) is indispensable for recruiting endogenous NuRD components. Mutation or deletion of SALL4's N-terminal NuRD-interacting motif abolishes reprogramming efficiency; grafting this motif onto Jdp2 partially rescues reprogramming, establishing the SALL4–NuRD axis as critical for chromatin closing during cell fate transition. ATAC-seq (chromatin accessibility), Co-IP (SALL4-NuRD), domain deletion/mutation, motif grafting rescue experiment, iPSC reprogramming efficiency assays Nature communications High 37208322
2018 SALL4 promotes gastric cancer metastasis by directly binding to the TGF-β1 gene promoter and activating its transcription, thereby activating TGF-β/SMAD signaling and inducing EMT; TGF-β1 knockdown reversed SALL4-mediated promotion of cancer cell motility. ChIP assay (SALL4 binding at TGF-β1 promoter), luciferase reporter assay, microarray, siRNA knockdown, in vivo peritoneal metastasis model Cancer management and research Medium 30349378
2016 SALL4 binds the CD44 promoter region and transcriptionally activates CD44 expression; CD44 overexpression rescued SALL4 knockdown-mediated inhibition of gastric cancer cell proliferation, migration, and invasion in vitro and in vivo, establishing CD44 as a functional downstream effector of SALL4. ChIP, luciferase reporter assay, shRNA knockdown with tetracycline-inducible system, CD44 rescue experiment, in vivo xenograft model Oncogenesis Medium 27819668
2020 SALL4 directly binds the HK-2 (hexokinase II) gene promoter and activates its transcription; HK-2 knockdown abrogated SALL4-promoted glycolysis and reversed SALL4-driven gastric cancer cell proliferation, migration, and invasion, establishing HK-2 as a downstream effector of SALL4-mediated Warburg effect. ChIP, luciferase reporter assay, microarray, glycolysis assays (glucose uptake, lactate, ATP, hexokinase activity), HK-2 rescue experiment, in vivo xenograft and peritoneal metastasis models Cancer cell international Medium 32489324
2013 SALL4 directly binds the c-Myc promoter region in endometrial cancer cells; SALL4 knockdown decreases c-Myc expression at both mRNA and protein levels, and SALL4 overexpression increases c-Myc, establishing c-Myc as a direct transcriptional target of SALL4 in endometrial tumorigenesis. ChIP, siRNA knockdown, SALL4 overexpression, qRT-PCR, Western blot, in vivo xenograft and metastasis models Oncogene Medium 24336327
2013 SALL4 suppresses CDH1 (E-cadherin) expression and positively regulates the CDH1 suppressor ZEB1 in basal-like breast cancer; SALL4 maintains cell dispersion by suppressing intercellular adhesion and cell motility after cell-cell interaction. shRNA knockdown, SALL4 overexpression, cell behavior analysis (adhesion, motility, dispersion assays), gene expression analysis FEBS letters Medium 23954296
2018 SALL4 upregulates KHDRBS3 (a splicing factor), which in turn modulates CD44 alternative splicing to produce a specific CD44 variant (CD44v lacking exons 8 and 9) that promotes cancer stemness and anoikis resistance in basal-like breast cancer. shRNA knockdown, gene overexpression, sphere formation assay, CD44 splicing isoform cloning and analysis, anoikis resistance assay Cancer medicine Medium 29356399
2021 SALL4 negatively regulates melanoma invasiveness through interaction with HDAC2 and direct co-binding to a set of invasiveness gene loci; SALL4 loss or HDAC inhibition promotes an invasive gene expression signature while inhibition of histone acetylation partially reverts SALL4 loss-induced invasiveness. ChIP (SALL4 and HDAC2 co-binding), transcriptional profiling, SALL4 knockout in melanoma mouse model, HDAC inhibitor treatment, in vitro invasion assays Nature communications High 34417458
2023 SALL4 directly binds the promoters of VEGF-A, VEGF-B, and VEGF-C genes and activates their transcription, associated with increased H3K79 and H3K4 histone modifications; SALL4-regulated VEGF expression promotes gastric cancer angiogenesis by recruiting endothelial cells. ChIP, EMSA (electrophoretic mobility shift assay), luciferase reporter assay, SALL4 knockdown/knockout/overexpression, HUVEC functional assays (proliferation, migration, tube formation), in vivo xenograft Cancer cell international Medium 37525212
2017 In Xenopus, sall4 (ortholog of mammalian SALL4) represses pou5f3 family gene expression (orthologs of Oct4/Pou5f1) in the neural plate; sall4 knockdown causes aberrant pou5f3 upregulation and defects in neural patterning, morphogenesis, and differentiation that phenocopy overexpression of pou5f3 genes. Morpholino knockdown of sall1/sall4, in situ hybridization, pou5f3 overexpression rescue/phenocopy experiments in Xenopus Developmental biology Medium 28322736
2020 Brg1 (BRG1/SMARCA4) directly binds the SALL4 promoter and enhances SALL4 transcription in HCC cells; miR-296-5p targets Brg1, thereby suppressing SALL4 expression and inhibiting HCC cancer stem cell stemness. ChIP (Brg1 binding to SALL4 promoter), luciferase reporter assay, miR-296-5p overexpression/knockdown, sphere formation assay, in vivo tumorigenesis in NOD/SCID mice Cellular signalling Medium 32320856

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 460 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
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
2019 SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC. Oncoimmunology 157 31143524
2006 Murine inner cell mass-derived lineages depend on Sall4 function. Proceedings of the National Academy of Sciences of the United States of America 156 17060609
2014 SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases. The American journal of surgical pathology 153 24525512
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
2005 Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nature genetics 137 16380715
2007 Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proceedings of the National Academy of Sciences of the United States of America 131 17557835
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
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
2008 Sall4 regulates cell fate decision in fetal hepatic stem/progenitor cells. Gastroenterology 94 19185577
2018 Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion. Nature communications 90 29593314
2013 SALL4 expression in gonocytes and spermatogonial clones of postnatal mouse testes. PloS one 88 23326552
2013 SALL4 is a new target in endometrial cancer. Oncogene 85 24336327
2016 The regulatory repertoire of PLZF and SALL4 in undifferentiated spermatogonia. Development (Cambridge, England) 83 27068105
2014 SALL4: an emerging cancer biomarker and target. Cancer letters 80 25444934
2018 SALL4 activates TGF-β/SMAD signaling pathway to induce EMT and promote gastric cancer metastasis. Cancer management and research 74 30349378
2013 Role of SALL4 in the progression and metastasis of colorectal cancer. Journal of biomedical science 73 23363002
2002 Cloning and expression analysis of SALL4, the murine homologue of the gene mutated in Okihiro syndrome. Cytogenetic and genome research 73 12826753
2006 Differential expression of the novel oncogene, SALL4, in lymphoma, plasma cell myeloma, and acute lymphoblastic leukemia. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 72 16998462
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 67 16899215
2017 Long noncoding RNA DANCR is activated by SALL4 and promotes the proliferation and invasion of gastric cancer cells. Oncotarget 64 29416741
2013 Low-expression of microRNA-107 inhibits cell apoptosis in glioma by upregulation of SALL4. The international journal of biochemistry & cell biology 63 23811124
2016 Sall4 controls differentiation of pluripotent cells independently of the Nucleosome Remodelling and Deacetylation (NuRD) complex. Development (Cambridge, England) 60 27471257
2011 Stem cell gene SALL4 suppresses transcription through recruitment of DNA methyltransferases. The Journal of biological chemistry 57 22128185
2017 Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes. Stem cell reports 56 28867346
2008 Sall1, sall2, and sall4 are required for neural tube closure in mice. The American journal of pathology 55 18818376
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 52 29976840
2019 Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Jdp2-Jhdm1b-Mkk6-Glis1-Nanog-Essrb-Sall4. Cell reports 44 31216469
2022 SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance. International journal of molecular sciences 42 35216168
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
2018 SALL4 - KHDRBS3 network enhances stemness by modulating CD44 splicing in basal-like breast cancer. Cancer medicine 40 29356399
2016 Maternal Sall4 Is Indispensable for Epigenetic Maturation of Mouse Oocytes. The Journal of biological chemistry 40 28031467
2014 The expression of SALL4 in patients with gliomas: high level of SALL4 expression is correlated with poor outcome. Journal of neuro-oncology 40 25359397
2020 SALL4 promotes gastric cancer progression via hexokinase II mediated glycolysis. Cancer cell international 39 32489324
2017 SALL4 suppresses PTEN expression to promote glioma cell proliferation via PI3K/AKT signaling pathway. Journal of neuro-oncology 38 28887597
2013 Sal-like 4 (SALL4) suppresses CDH1 expression and maintains cell dispersion in basal-like breast cancer. FEBS letters 38 23954296
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 34 33406384
2020 miR-296-5p suppresses stem cell potency of hepatocellular carcinoma cells via regulating Brg1/Sall4 axis. Cellular signalling 33 32320856
2016 Targeting SALL4 by entinostat in lung cancer. Oncotarget 33 27705911
2017 SALL4 promotes glycolysis and chromatin remodeling via modulating HP1α-Glut1 pathway. Oncogene 32 28759035
2017 The stem cell factor SALL4 is an essential transcriptional regulator in mixed lineage leukemia-rearranged leukemogenesis. Journal of hematology & oncology 31 28974232
2016 DNA demethylation induces SALL4 gene re-expression in subgroups of hepatocellular carcinoma associated with Hepatitis B or C virus infection. Oncogene 31 27797380
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
2023 The NuRD complex cooperates with SALL4 to orchestrate reprogramming. Nature communications 29 37208322
2014 Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: mechanism, function, and implication for a potential novel therapeutic target. Experimental hematology 28 24463278
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
2020 SALL4 promotes tumor progression in breast cancer by targeting EMT. Molecular carcinogenesis 27 32835442
2015 SALL4 is a novel therapeutic target in intrahepatic cholangiocarcinoma. Oncotarget 27 26317546
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
2016 Expression and clinical significance of SALL4 and β-catenin in colorectal cancer. Journal of molecular histology 25 26779651
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
2024 SALL4 promotes cancer stem-like cell phenotype and radioresistance in oral squamous cell carcinomas via methyltransferase-like 3-mediated m6A modification. Cell death & disease 21 38355684
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
2021 Sall4 and Myocd Empower Direct Cardiac Reprogramming From Adult Cardiac Fibroblasts After Injury. Frontiers in cell and developmental biology 20 33718351
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
2020 Upregulation of SNHG12 accelerates cell proliferation, migration, invasion and restrain cell apoptosis in breast cancer by enhancing regulating SALL4 expression via sponging miR-15a-5p. Neoplasma 20 32386479
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
2020 VHL mutation-mediated SALL4 overexpression promotes tumorigenesis and vascularization of clear cell renal cell carcinoma via Akt/GSK-3β signaling. Journal of experimental & clinical cancer research : CR 19 32513235
2014 Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner. Experimental hematology 19 25246269
2023 SALL4 promotes angiogenesis in gastric cancer by regulating VEGF expression and targeting SALL4/VEGF pathway inhibits cancer progression. Cancer cell international 18 37525212
2020 Effect of SALL4 on the Proliferation, Invasion and Apoptosis of Breast Cancer Cells. Technology in cancer research & treatment 17 33308020
2018 SALL4 suppresses reactive oxygen species in pancreatic ductal adenocarcinoma phenotype via FoxM1/Prx III axis. Biochemical and biophysical research communications 17 29958885
2017 sall1 and sall4 repress pou5f3 family expression to allow neural patterning, differentiation, and morphogenesis in Xenopus laevis. Developmental biology 17 28322736
2012 The differential expression pattern of the BMI-1, SALL4 and ABCA3 genes in myeloid leukemia. Cancer cell international 17 23067006
2023 The new advance of SALL4 in cancer: Function, regulation, and implication. Journal of clinical laboratory analysis 16 37337914
2021 SALL-4 and Beta-Catenin Expression in Sinonasal Teratocarcinosarcoma. Head and neck pathology 16 34106411
2016 Functional and clinical significance of SALL4 in breast cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 27444278
2014 SALL4: engine of cell stemness. Current gene therapy 16 25174577
2014 Clinicopathologic characteristics of SALL4-immunopositive hepatocellular carcinoma. SpringerPlus 16 26034695
2012 Role of SALL4 in hematopoiesis. Current opinion in hematology 16 22555391
2019 The role of ESCO2, SALL4 and TBX5 genes in the susceptibility to thalidomide teratogenesis. Scientific reports 15 31388035
2015 Knockdown of SALL4 Protein Enhances All-trans Retinoic Acid-induced Cellular Differentiation in Acute Myeloid Leukemia Cells. The Journal of biological chemistry 15 25737450
2014 The next new target in leukemia: The embryonic stem cell gene SALL4. Molecular & cellular oncology 15 25977939
2013 Expression of sall4 in taste buds of zebrafish. Developmental neurobiology 15 23447551

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