Genome-Wide Analysis of Smad7-Mediated Transcription in Mouse Embryonic Stem Cells

Meng, Guohua; Lauria, Andrea; Maldotti, Mara; Anselmi, Francesca; Polignano, Isabelle Laurence; Rapelli, Stefania; Donna, Daniela; Oliviero, Salvatore

doi:10.3390/ijms222413598

Cited by 4 publications

(5 citation statements)

References 47 publications

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“…In agreement with this hypothesis lncSmad7 knockout resulted in the reduction of acetylation in several genomic loci ( Supplementary Figure S4A ). To verify the hypothesis that lncSmad7 regulates the transcription of other genes besides Smad7 , we first sought to uncouple the contribution to gene expression of lncSmad7 from those regulated by Smad7 ( 60 ). To this end, we compared the RNA expression profiles of WT ESCs with lncSmad7 KO, and the lncSmad7 KO ectopically expressing either lncSmad7 or Smad7 ( Supplementary Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

The acetyltransferase p300 is recruited in trans to multiple enhancer sites by lncSmad7

Maldotti

Lauria

Anselmi

et al. 2022

Nucleic Acids Research

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The histone acetyltransferase p300 (also known as KAT3B) is a general transcriptional coactivator that introduces the H3K27ac mark on enhancers triggering their activation and gene transcription. Genome-wide screenings demonstrated that a large fraction of long non-coding RNAs (lncRNAs) plays a role in cellular processes and organ development although the underlying molecular mechanisms remain largely unclear (1,2). We found 122 lncRNAs that interacts directly with p300. In depth analysis of one of these, lncSmad7, is required to maintain ESC self-renewal and it interacts to the C-terminal domain of p300. lncSmad7 also contains predicted RNA-DNA Hoogsteen forming base pairing. Combined Chromatin Isolation by RNA precipitation followed by sequencing (ChIRP-seq) together with CRISPR/Cas9 mutagenesis of the target sites demonstrate that lncSmad7 binds and recruits p300 to enhancers in trans, to trigger enhancer acetylation and transcriptional activation of its target genes. Thus, these results unveil a new mechanism by which p300 is recruited to the genome.

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Section: Resultsmentioning

confidence: 99%

The acetyltransferase p300 is recruited in trans to multiple enhancer sites by lncSmad7

Maldotti

Lauria

Anselmi

et al. 2022

Nucleic Acids Research

Self Cite

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“…Recent studies have shown that Smad7 can act as a general transcription factor regulating several genes that are unrelated to the TGF-β1 pathway [ 23 ]. Therefore, we next evaluated whether the reduced Stat3 content seen in Smad7-deficient cells was secondary to the regulation of Stat3 RNA expression by Smad7.…”

Section: Resultsmentioning

confidence: 99%

“…The ability of Smad7 to act as a transcription factor has been previously shown in prostatic cancer cells, where Smad7 can bind the regulatory regions and enhance the expression of c-Jun and Histone deacetylase 6, two tumor-promoting genes [ 18 ]. Along the same lines is the demonstration that in mouse embryonic stem cells, Smad7 occupies the promoters of highly expressed key stemness regulators genes by binding to a specific consensus response element, NCGGAAMM [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells

Maresca

Maggio

Stolfi

et al. 2022

Cancers

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Colorectal cancer (CRC) cells contain elevated levels of active signal transducer and the activator of transcription (Stat)-3, which exerts proliferative and anti-apoptotic effects. Various molecules produced in the CRC tissue can activate Stat3, but the mechanisms that amplify such an activation are yet to be determined. In this paper, we assessed whether Smad7, an inhibitor of Transforiming Growth Factor (TGF)-β1 activity, sustains Stat3 expression/activation in CRC cells. Both Smad7 and phosphorylated (p)/activated-Stat3 were more expressed in the tumoral areas of CRC patients, compared to the normal adjacent colonic mucosa of the same patients, and were co-localized in primary CRC cells and CRC cell lines. The knockdown of Smad7 with a Smad7 antisense oligonucleotide (AS) reduced p-Stat3 in both unstimulated and interleukin (IL)-6- and IL-22-stimulated DLD-1 and HCT116 cells. Consistently, reduced levels of BCL-xL and survivin, two downstream signaling targets of Stat3 activation, were seen in Smad7 AS-treated cells. An analysis of the mechanisms underlying Smad7 AS-induced Stat3 inactivation revealed that Smad7 AS reduced Stat3 RNA and protein expression. A chromatin immunoprecipitation assay showed the direct regulatory effect of Smad7 on the Stat3 promoter. RNA-sequencing data from the Tumor, Normal and Metastatic (TNM) plot database showed a positive correlation between Smad7 and Stat3 in 1450 CRC samples. To our knowledge, this is the first evidence supporting the theory that Smad7 positively regulates Stat3 function in CRC.

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“…In contrast, macrophage-specific SMAD7 deletion did not affect alanine aminotransferase (ALT) and aspartate transferase (AST) levels, inflammatory cell infiltration, and fibrosis degree in CCL 4 -induced chronic liver injury mouse models 101 . In addition, the evidence also demonstrates that SMAD7 can bind to the self-renewal genes Nanog, sex determining region Y-box 2 (Sox2), and inhibitor of DNA binding 2 (ID2) in embryonic stem cells (ESCs), regulating the self-renewal and pluripotency of ESCs 102 .…”

Section: The Functional Role Of the Tgf-β/smad Signaling Pathway In Hccmentioning

confidence: 99%

The Role of TGF-β/SMAD Signaling in Hepatocellular Carcinoma: from Mechanism to Therapy and Prognosis

Xin,

Cheng,

Zeng

et al. 2024

Int. J. Biol. Sci.

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with high incidence and mortality, accounting for approximately 90% of liver cancer. The development of HCC is a complex process involving the abnormal activation or inactivation of multiple signaling pathways. Transforming growth factor-β (TGF-β)/Small mothers against decapentaplegic (SMAD) signaling pathway regulates the development of HCC. TGF-β activates intracellular SMADs protein through membrane receptors, resulting in a series of biological cascades. Accumulating studies have demonstrated that TGF-β/SMAD signaling plays multiple regulatory functions in HCC. However, there is still controversy about the role of TGF-β/SMAD in HCC. Because it involves different pathogenic factors, disease stages, and cell microenvironment, as well as upstream and downstream relationships with other signaling pathways. This review will summary the regulatory mechanism of the TGF-β/SMAD signaling pathway in HCC, involving the regulation of different pathogenic factors, different disease stages, different cell populations, microenvironments, and the interaction with microRNAs. In addition, we also introduced small molecule inhibitors, therapeutic vaccines, and traditional Chinese medicine extracts based on targeting the TGF-β/SMAD signaling pathway, which will provide future research direction for HCC therapy targeting the TGF-β/SMAD signaling pathway.

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Genome-Wide Analysis of Smad7-Mediated Transcription in Mouse Embryonic Stem Cells

Cited by 4 publications

References 47 publications

The acetyltransferase p300 is recruited in trans to multiple enhancer sites by lncSmad7

The acetyltransferase p300 is recruited in trans to multiple enhancer sites by lncSmad7

Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells

The Role of TGF-β/SMAD Signaling in Hepatocellular Carcinoma: from Mechanism to Therapy and Prognosis

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