SMAD3 Transcription Factor
SMAD family member 3 | HsT17436, JV15-2, MADH3

The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

Member of: DE-4 DE-4.13
Biological processes 180 terms
DEAD/H-box RNA helicase binding (GO:0017151)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 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 (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-binding transcription factor activity, RNA polymerase II-specific (GO:0000981)DNA-binding transcription factor binding (GO:0140297)DNA-binding transcription repressor activity (GO:0001217)I-SMAD binding (GO:0070411)JNK cascade (GO:0007254)MAPK cascade (GO:0000165)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 transcription regulatory region sequence-specific DNA binding (GO:0000977)RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629)RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629)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)T cell activation (GO:0042110)activin receptor signaling pathway (GO:0032924)activin receptor signaling pathway (GO:0032924)activin receptor signaling pathway (GO:0032924)adrenal gland development (GO:0030325)anatomical structure morphogenesis (GO:0009653)apoptotic signaling pathway (GO:0097190)bHLH transcription factor binding (GO:0043425)beta-catenin binding (GO:0008013)cell differentiation (GO:0030154)cell-cell junction organization (GO:0045216)cellular response to glucose stimulus (GO:0071333)cellular response to growth factor stimulus (GO:0071363)cellular response to platelet-derived growth factor stimulus (GO:0036120)cellular response to transforming growth factor beta stimulus (GO:0071560)cellular response to transforming growth factor beta stimulus (GO:0071560)cellular response to virus (GO:0098586)chromatin (GO:0000785)chromatin (GO:0000785)chromatin DNA binding (GO:0031490)chromatin binding (GO:0003682)cis-regulatory region sequence-specific DNA binding (GO:0000987)cis-regulatory region sequence-specific DNA binding (GO:0000987)cis-regulatory region sequence-specific DNA binding (GO:0000987)co-SMAD binding (GO:0070410)collagen binding (GO:0005518)cytoplasm (GO:0005737)cytoplasm (GO:0005737)cytoplasm (GO:0005737)cytosol (GO:0005829)cytosol (GO:0005829)developmental process (GO:0032502)double-stranded DNA binding (GO:0003690)enzyme binding (GO:0019899)extrinsic apoptotic signaling pathway (GO:0097191)extrinsic apoptotic signaling pathway (GO:0097191)gene expression (GO:0010467)heteromeric SMAD protein complex (GO:0071144)heteromeric SMAD protein complex (GO:0071144)identical protein binding (GO:0042802)identical protein binding (GO:0042802)immune response (GO:0006955)negative regulation of apoptotic process (GO:0043066)negative regulation of cardiac muscle hypertrophy in response to stress (GO:1903243)negative regulation of cell differentiation (GO:0045596)negative regulation of cell growth (GO:0030308)negative regulation of cell population proliferation (GO:0008285)negative regulation of cell population proliferation (GO:0008285)negative regulation of cytosolic calcium ion concentration (GO:0051481)negative regulation of fat cell differentiation (GO:0045599)negative regulation of gene expression (GO:0010629)negative regulation of inflammatory response (GO:0050728)negative regulation of inflammatory response (GO:0050728)negative regulation of lipopolysaccharide-mediated signaling pathway (GO:0031665)negative regulation of lung blood pressure (GO:0061767)negative regulation of miRNA transcription (GO:1902894)negative regulation of ossification (GO:0030279)negative regulation of osteoblast proliferation (GO:0033689)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)negative regulation of transcription by RNA polymerase II (GO:0000122)negative regulation of transforming growth factor beta production (GO:0071635)negative regulation of wound healing (GO:0061045)nodal signaling pathway (GO:0038092)nuclear glucocorticoid receptor binding (GO:0035259)nuclear inner membrane (GO:0005637)nuclear mineralocorticoid receptor binding (GO:0031962)nuclear receptor binding (GO:0016922)nucleoplasm (GO:0005654)nucleoplasm (GO:0005654)nucleus (GO:0005634)nucleus (GO:0005634)nucleus (GO:0005634)nucleus (GO:0005634)osteoblast differentiation (GO:0001649)phosphatase binding (GO:0019902)plasma membrane (GO:0005886)positive regulation of DNA-templated transcription (GO:0045893)positive regulation of SMAD protein signal transduction (GO:0060391)positive regulation of bone mineralization (GO:0030501)positive regulation of canonical Wnt signaling pathway (GO:0090263)positive regulation of cell migration (GO:0030335)positive regulation of chondrocyte differentiation (GO:0032332)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 extracellular matrix assembly (GO:1901203)positive regulation of focal adhesion assembly (GO:0051894)positive regulation of gene expression (GO:0010628)positive regulation of interleukin-1 beta production (GO:0032731)positive regulation of miRNA transcription (GO:1902895)positive regulation of miRNA transcription (GO:1902895)positive regulation of miRNA transcription (GO:1902895)positive regulation of nitric oxide biosynthetic process (GO:0045429)positive regulation of nitric oxide biosynthetic process (GO:0045429)positive regulation of positive chemotaxis (GO:0050927)positive regulation of protein import into nucleus (GO:0042307)positive regulation of stress fiber assembly (GO:0051496)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 transcription by RNA polymerase II (GO:0045944)positive regulation of transforming growth factor beta3 production (GO:0032916)primary miRNA processing (GO:0031053)promoter-specific chromatin binding (GO:1990841)protein binding (GO:0005515)protein homodimerization activity (GO:0042803)protein kinase binding (GO:0019901)protein stabilization (GO:0050821)protein-DNA complex (GO:0032993)regulation of DNA-templated transcription (GO:0006355)regulation of DNA-templated transcription (GO:0006355)regulation of DNA-templated transcription (GO:0006355)regulation of dendritic spine morphogenesis (GO:0061001)regulation of immune response (GO:0050776)regulation of miRNA transcription (GO:1902893)regulation of mitochondrial membrane potential (GO:0051881)regulation of transcription by RNA polymerase II (GO:0006357)regulation of transforming growth factor beta2 production (GO:0032909)release of cytochrome c from mitochondria (GO:0001836)response to alcohol (GO:0097305)response to angiotensin (GO:1990776)response to cocaine (GO:0042220)response to gamma radiation (GO:0010332)response to hypoxia (GO:0001666)sequence-specific DNA binding (GO:0043565)sequence-specific DNA binding (GO:0043565)signal transduction involved in regulation of gene expression (GO:0023019)signaling receptor complex (GO:0043235)sterol response element binding (GO:0032810)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)transdifferentiation (GO:0060290)transforming growth factor beta receptor binding (GO:0005160)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)trophoblast cell migration (GO:0061450)ubiquitin binding (GO:0043130)ubiquitin protein ligase binding (GO:0031625)ureteric bud development (GO:0001657)wound healing (GO:0042060)zinc ion binding (GO:0008270)
Expression (TPM)
SMAD3 — as a Regulator

Modules regulated by SMAD3

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 SMAD3

Genes likely regulated by SMAD3 through linked binding evidence in open chromatin. The chart ranks TF-linked genes by their mean Perturb-seq response to SMAD3 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 SMAD3 has ChIP-seq or motif footprint binding evidence and which are linked to at least one target gene region.

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SMAD3 — as a Regulated Gene

TFs regulating SMAD3 0 TFs

Transcription factors with Perturb-seq knockdown data for SMAD3. 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 = SMAD3 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 SMAD3

Open chromatin peaks (ATAC-seq) in the genomic neighbourhood of SMAD3, 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
chr15:66,773,918–66,774,633 291.1 kb Distal (>10kb) Multiome 524
chr15:66,842,072–66,842,664 222.9 kb Distal (>10kb) Multiome 519
chr15:66,842,765–66,843,830 222.3 kb Distal (>10kb) Multiome 413
chr15:66,923,439–66,924,007 141.9 kb Distal (>10kb) Multiome 191
chr15:66,927,757–66,928,460 137.3 kb Distal (>10kb) Multiome 77
chr15:67,029,958–67,030,628 35.1 kb Distal (>10kb) Multiome 394
chr15:67,063,703–67,064,666 1.3 kb Proximal (<10kb) Multiome HiCAR 769
chr15:67,064,798–67,066,190 27 bp At TSS Multiome HiCAR 881
chr15:67,067,506–67,068,588 2.6 kb Proximal (<10kb) Multiome HiCAR 341
chr15:67,070,163–67,070,402 6.4 kb Proximal (<10kb) 48
chr15:67,071,011–67,071,208 7.2 kb Proximal (<10kb) 30
chr15:67,086,180–67,086,640 20.8 kb Distal (>10kb) Multiome HiCAR 143
chr15:67,152,836–67,153,778 87.7 kb Distal (>10kb) Multiome 90
chr15:67,164,757–67,165,266 99.2 kb Distal (>10kb) Multiome HiCAR 99
chr15:67,165,558–67,166,225 100.3 kb Distal (>10kb) Multiome 151
chr15:67,254,178–67,255,165 189.1 kb Distal (>10kb) Multiome 964
chr15:67,267,516–67,268,376 202.3 kb Distal (>10kb) Multiome 61

Genome Browser

Genomic view of the SMAD3 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.

chr15:66,763,918 – 67,278,376
Proximal 1 kb Distal 10 kb Multiome HiCAR ATAC-seq RNA-seq