SMAD4 Transcription Factor
SMAD family member 4 | DPC4, MADH4

This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, May 2022]

Member of: DE-5
Biological processes 150 terms
BMP signaling pathway (GO:0030509)BMP signaling pathway (GO:0030509)BMP signaling pathway (GO:0030509)BMP signaling pathway (GO:0030509)BMP signaling pathway (GO:0030509)BMP signaling pathway (GO:0030509)DNA binding (GO:0003677)DNA binding (GO:0003677)DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228)DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228)DNA-binding transcription factor activity (GO:0003700)DNA-binding transcription factor activity (GO:0003700)DNA-binding transcription factor activity (GO:0003700)DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981)DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981)DNA-templated transcription (GO:0006351)DNA-templated transcription (GO:0006351)ERK1 and ERK2 cascade (GO:0070371)I-SMAD binding (GO:0070411)I-SMAD binding (GO:0070411)R-SMAD binding (GO:0070412)RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978)RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978)RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978)RNA polymerase II transcription regulator complex (GO:0090575)RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977)RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629)SMAD binding (GO:0046332)SMAD protein complex (GO:0071141)SMAD protein complex (GO:0071141)SMAD protein signal transduction (GO:0060395)SMAD protein signal transduction (GO:0060395)SMAD protein signal transduction (GO:0060395)SMAD protein signal transduction (GO:0060395)SMAD protein signal transduction (GO:0060395)activin receptor signaling pathway (GO:0032924)activin responsive factor complex (GO:0032444)adrenal gland development (GO:0030325)anatomical structure morphogenesis (GO:0009653)atrioventricular canal development (GO:0036302)atrioventricular canal development (GO:0036302)atrioventricular valve formation (GO:0003190)atrioventricular valve formation (GO:0003190)cardiac conduction system development (GO:0003161)cardiac muscle hypertrophy in response to stress (GO:0014898)cardiac septum development (GO:0003279)cell differentiation (GO:0030154)cellular response to BMP stimulus (GO:0071773)cellular response to glucose stimulus (GO:0071333)cellular response to growth factor stimulus (GO:0071363)cellular response to transforming growth factor beta stimulus (GO:0071560)chromatin (GO:0000785)chromatin (GO:0000785)chromatin binding (GO:0003682)collagen binding (GO:0005518)cytoplasm (GO:0005737)cytoplasm (GO:0005737)cytosol (GO:0005829)cytosol (GO:0005829)embryonic digit morphogenesis (GO:0042733)endocardial cell differentiation (GO:0060956)endocardial cell differentiation (GO:0060956)endothelial cell activation (GO:0042118)epithelial cell migration (GO:0010631)epithelial to mesenchymal transition (GO:0001837)epithelial to mesenchymal transition (GO:0001837)epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198)extrinsic apoptotic signaling pathway (GO:0097191)filamin binding (GO:0031005)heteromeric SMAD protein complex (GO:0071144)identical protein binding (GO:0042802)identical protein binding (GO:0042802)interleukin-6-mediated signaling pathway (GO:0070102)interleukin-6-mediated signaling pathway (GO:0070102)intracellular iron ion homeostasis (GO:0006879)intracellular iron ion homeostasis (GO:0006879)intracellular signal transduction (GO:0035556)left ventricular cardiac muscle tissue morphogenesis (GO:0003220)left ventricular cardiac muscle tissue morphogenesis (GO:0003220)metanephric mesenchyme morphogenesis (GO:0072133)negative regulation of DNA-templated transcription (GO:0045892)negative regulation of ERK1 and ERK2 cascade (GO:0070373)negative regulation of ERK1 and ERK2 cascade (GO:0070373)negative regulation of canonical Wnt signaling pathway (GO:0090090)negative regulation of cardiac muscle hypertrophy (GO:0010614)negative regulation of cardiac muscle hypertrophy (GO:0010614)negative regulation of cardiac myofibril assembly (GO:1905305)negative regulation of cardiac myofibril assembly (GO:1905305)negative regulation of cell growth (GO:0030308)negative regulation of protein catabolic process (GO:0042177)negative regulation of transcription by RNA polymerase II (GO:0000122)negative regulation of transcription by RNA polymerase II (GO:0000122)nephrogenic mesenchyme morphogenesis (GO:0072134)neuron fate specification (GO:0048665)nucleoplasm (GO:0005654)nucleoplasm (GO:0005654)nucleus (GO:0005634)nucleus (GO:0005634)osteoblast differentiation (GO:0001649)outflow tract septum morphogenesis (GO:0003148)outflow tract septum morphogenesis (GO:0003148)ovarian follicle development (GO:0001541)positive regulation of DNA-templated transcription (GO:0045893)positive regulation of SMAD protein signal transduction (GO:0060391)positive regulation of SMAD protein signal transduction (GO:0060391)positive regulation of cardiac muscle cell apoptotic process (GO:0010666)positive regulation of cell population proliferation (GO:0008284)positive regulation of cell population proliferation (GO:0008284)positive regulation of cell proliferation involved in heart morphogenesis (GO:2000138)positive regulation of cell proliferation involved in heart morphogenesis (GO:2000138)positive regulation of epithelial to mesenchymal transition (GO:0010718)positive regulation of epithelial to mesenchymal transition (GO:0010718)positive regulation of extracellular matrix assembly (GO:1901203)positive regulation of gene expression (GO:0010628)positive regulation of miRNA transcription (GO:1902895)positive regulation of transcription by RNA polymerase II (GO:0045944)positive regulation of transcription by RNA polymerase II (GO:0045944)positive regulation of transcription by RNA polymerase II (GO:0045944)positive regulation of transforming growth factor beta receptor signaling pathway (GO:0030511)protein binding (GO:0005515)protein homodimerization activity (GO:0042803)protein-containing complex (GO:0032991)protein-containing complex binding (GO:0044877)regulation of DNA-templated transcription (GO:0006355)regulation of DNA-templated transcription (GO:0006355)regulation of gene expression (GO:0010468)regulation of transcription by RNA polymerase II (GO:0006357)regulation of transforming growth factor beta2 production (GO:0032909)response to hypoxia (GO:0001666)response to transforming growth factor beta (GO:0071559)secondary palate development (GO:0062009)secondary palate development (GO:0062009)sequence-specific DNA binding (GO:0043565)sulfate binding (GO:0043199)transcription cis-regulatory region binding (GO:0000976)transcription coactivator binding (GO:0001223)transcription corepressor binding (GO:0001222)transcription regulator complex (GO:0005667)transcription regulator complex (GO:0005667)transcription regulator complex (GO:0005667)transforming growth factor beta receptor signaling pathway (GO:0007179)transforming growth factor beta receptor signaling pathway (GO:0007179)transforming growth factor beta receptor signaling pathway (GO:0007179)transforming growth factor beta receptor signaling pathway (GO:0007179)transforming growth factor beta receptor signaling pathway (GO:0007179)transforming growth factor beta receptor signaling pathway (GO:0007179)transforming growth factor beta receptor signaling pathway (GO:0007179)transforming growth factor beta receptor superfamily signaling pathway (GO:0141091)ventricular septum morphogenesis (GO:0060412)ventricular septum morphogenesis (GO:0060412)
Expression (TPM)
SMAD4 — as a Regulator

Modules regulated by SMAD4

Modules significantly affected by knockdown. ↑ Up = module upregulated upon KD; ↓ Down = module downregulated upon KD.

Evidence: Direction:
Perturbation + Binding
Perturbation only
Binding only
Cluster Dir NES padj Bind OR padj (bind)
Evidence: Direction:
Perturbation + Binding
Perturbation only
Binding only
Module Dir NES #gRNA padj Bind OR padj (bind)
Evidence: Direction: Max shown:
Perturbation + Binding
Perturbation only
Binding only
Submodule Module Dir NES #gRNA Bind OR padj (bind)

Genes regulated by SMAD4

Genes likely regulated by SMAD4 through linked binding evidence in open chromatin. The chart ranks TF-linked genes by their mean Perturb-seq response to SMAD4 knockdown, with negative coefficients indicating downregulation and positive coefficients indicating upregulation upon knockdown.

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Regulatory Elements bound by the TF

Open chromatin elements (ATAC-seq) where SMAD4 has ChIP-seq or motif footprint binding evidence and which are linked to at least one target gene region.

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SMAD4 — as a Regulated Gene

TFs regulating SMAD4 0 TFs

Transcription factors with Perturb-seq knockdown data for SMAD4. The Binding column indicates whether any binding evidence exists for this TF–gene pair (ChIP-seq or motif footprint peaks). The Mean coef is the average Perturb-seq regression coefficient across active gRNAs (positive = SMAD4 upregulated upon KD; negative = downregulated). The Outlier column indicates whether this gene is in the top or bottom 5% of all TF knockdown effects.

Data: Effect:
TF Mean coef Binding Outlier TF→Gene link

Elements linked to SMAD4

Open chromatin peaks (ATAC-seq) in the genomic neighbourhood of SMAD4, linked by TSS proximity or chromatin conformation (Multiome / HiCAR). Each element overlaps at least one TF ChIP-seq binding site — the TFs column shows how many distinct TFs bind that element.

Accessibility Element Dist. to TSS Link type TFs
chr18:50,748,143–50,748,985 281.7 kb Distal (>10kb) Multiome 312
chr18:50,784,562–50,785,070 245.3 kb Distal (>10kb) Multiome 166
chr18:50,806,171–50,806,699 223.8 kb Distal (>10kb) Multiome 252
chr18:50,819,413–50,820,437 210.2 kb Distal (>10kb) Multiome HiCAR 590
chr18:50,878,372–50,880,419 150.1 kb Distal (>10kb) Multiome 895
chr18:50,899,511–50,900,194 130.4 kb Distal (>10kb) Multiome 71
chr18:50,967,806–50,968,647 62.1 kb Distal (>10kb) Multiome 840
chr18:50,992,154–50,992,773 37.6 kb Distal (>10kb) Multiome 86
chr18:51,006,448–51,007,439 23.1 kb Distal (>10kb) Multiome 157
chr18:51,025,638–51,025,859 4.4 kb Proximal (<10kb) 15
chr18:51,029,502–51,031,292 44 bp At TSS Multiome 813
chr18:51,039,296–51,039,660 9.1 kb Proximal (<10kb) 79
chr18:51,110,028–51,110,847 80.3 kb Distal (>10kb) Multiome 407
chr18:51,167,965–51,168,697 138.0 kb Distal (>10kb) Multiome 104
chr18:51,196,412–51,198,613 167.7 kb Distal (>10kb) Multiome 939

Genome Browser

Genomic view of the SMAD4 locus showing ATAC-seq accessibility and RNA-seq expression across the ESC → DE time course, together with TF binding peaks and element-to-TSS loop connections.

chr18:50,738,143 – 51,208,613
Proximal 1 kb Distal 10 kb Multiome HiCAR ATAC-seq RNA-seq