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]
Modules significantly affected by knockdown. ↑ Up = module upregulated upon KD; ↓ Down = module downregulated upon KD.
| Cluster | Dir | NES | padj | Bind | OR | padj (bind) |
|---|
| Module | Dir | NES | #gRNA | padj | Bind | OR | padj (bind) |
|---|
| Submodule | Module | Dir | NES | #gRNA | Bind | OR | padj (bind) |
|---|
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.
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.
| Element | Size | Linked genes |
|---|
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.
| TF | Mean coef | Binding | Outlier | TF→Gene link |
|---|
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 |
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.