TBX2 and TBX3 act downstream of canonical WNT signaling in patterning and differentiation of the mouse ureteric mesenchyme

Aydoğdu, Nurullah; Rudat, Carsten; Trowe, Mark Oliver; Kaiser, Marina; Lüdtke, Timo H.-W.; Taketo, Makoto Mark; Christoffels, Vincent M.; Moon, Anne M.; Kispert, Andreas

doi:10.1242/dev.171827

Cited by 35 publications

(36 citation statements)

References 69 publications

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“…We verified that Tbx3 is a target of Wnt signaling in the liver, by either over-activating or eliminating the Wnt pathway in the tissue (Figure. 1A, arrows point to TBX3 + Apc KO cells, arrowheads point to TBX3 - Wls KO cells), in agreement with data from other contexts (Aydoğdu et al 2018; Eblaghie et al 2004; Renard et al 2007; Waghray et al 2015). To examine the function of TBX3 in hepatocytes, we employed a recently developed method for long-term culture and genetic manipulation of primary hepatocytes, where cells multiply rapidly in a Wnt-dependent manner (Peng et al 2018).…”

Section: Resultssupporting

confidence: 88%

Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling

Jin

Anbarchian

et al. 2021

Preprint

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Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition. In several tissues including the liver, transcriptional repressors such as E2F7 and E2F8 function as inhibitors of mitosis and promote polyploidy, but how growth factors release these mitotic inhibitors to facilitate cell cycle progression is unknown. We describe here a newly identified mechanism of cell division control in which Wnt/βcatenin signaling in the postnatal liver maintains active hepatocyte proliferation through Tbx3, a Wnt target gene. TBX3 directly represses transcription of E2f7 and E2f8, promoting a low ploidy state and cell cycle progression. This sequential transcriptional repressor cascade, initiated by Wnts, provides a new paradigm for exploring how a commonly active developmental signal impacts cell cycle completion.

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Section: Resultssupporting

confidence: 88%

Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling

Jin

Anbarchian

et al. 2021

Preprint

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“…Our analysis provides further support to the genes associated with vascular remodeling ( COL4A1/2 , FURIN ) and transcriptional regulation ( FHL3 , KLF4 , ARNTL ) but also highlights new candidates with potentially similar roles ( TBX2 , LOXL1, SNHG18 ) that have not been previously associated with CAD. 8 For example, TBX2 (T-box transcription factor 2) has been extensively studied in the development of myocardium but emerging evidence also supports its importance in differentiation and functionality of smooth muscle cells 67 , 68 that warrant further research in the context of atherosclerosis. We also identified several novel target genes with no reported biological function but rather additional associations that could provide mechanistic insight.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Epigenomics and Functional Fine-Mapping of Atherosclerosis GWAS Loci

Örd

Õunap

Stolze

et al. 2021

Circulation Research

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Rationale: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD). Many of these loci are enriched in cis-regulatory elements (CREs) but not linked to cardiometabolic risk factors nor to candidate causal genes, complicating their functional interpretation. Objective: Single nucleus chromatin accessibility profiling of the human atherosclerotic lesions was used to investigate cell type-specific patterns of CREs, to understand transcription factors establishing cell identity and to interpret CAD-relevant, non-coding genetic variation. Methods and Results: We used single nucleus ATAC-seq to generate DNA accessibility maps in > 7,000 cells derived from human atherosclerotic lesions. We identified five major lesional cell types including endothelial cells, smooth muscle cells, monocyte/macrophages, NK/T-cells and B-cells and further investigated subtype characteristics of macrophages and smooth muscle cells transitioning into fibromyocytes. We demonstrated that CAD associated genetic variants are particularly enriched in endothelial and smooth muscle cell-specific open chromatin. Using single cell co-accessibility and cis-eQTL information, we prioritized putative target genes and candidate regulatory elements for ~30% of all known CAD loci. Finally, we performed genome-wide experimental fine-mapping of the CAD GWAS variants using epigenetic QTL analysis in primary human aortic endothelial cells and STARR-Seq massively parallel reporter assay in smooth muscle cells. This analysis identified potential causal SNP(s) and the associated target gene for over 30 CAD loci. We present several examples where the chromatin accessibility and gene expression could be assigned to one cell type predicting the cell type of action for CAD loci. Conclusions: These findings highlight the potential of applying snATAC-seq to human tissues in revealing relative contributions of distinct cell types to diseases and in identifying genes likely to be influenced by non-coding GWAS variants.

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“…"Abnormal pulmonary trunk morphology" and "dilated respiratory conducting tubes" were the top enriched clusters in mouse phenotypes indicating significant affiliation of TBX2-bound regions to pulmonary development. Additional peak clusters were affiliated with the terms "abnormal digit development", "failure of palatal shelf elevation", "development of the urogenital system" and "limbs" reflecting known functions of TBX2 in mouse development [37][38][39][40]. "Abnormal otic vesicle development", "decreased cochlear coiling" and "abnormal tympanic membrane morphology" within the top We next performed de novo sequence motif analysis on the sequenced tags with the FIMO tool in Galaxy [22] (Fig.…”

Section: Chip-seq Analysis Identifies Genome-wide Tbx2 Binding Sites mentioning

confidence: 99%

“…Second, we recovered binding peaks in those genes previously characterized as direct targets of TBX2 repressive activity in the lung, including Cdkn1a, Shisa3 and Frzb [13,15]. Third, GO annotation of biological function and processes revealed enrichment of peak-associated genes with mouse phenotypes previously associated with TBX2 function in various embryological contexts [37][38][39][40].…”

Section: Il33 and Ccn4 Are Novel Direct Targets Of Tbx2 In The Lung Mmentioning

confidence: 99%

Combined genomic and proteomic approaches reveal DNA binding sites and interaction partners of TBX2 in the developing lung

et al. 2021

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Background Tbx2 encodes a transcriptional repressor implicated in the development of numerous organs in mouse. During lung development TBX2 maintains the proliferation of mesenchymal progenitors, and hence, epithelial proliferation and branching morphogenesis. The pro-proliferative function was traced to direct repression of the cell-cycle inhibitor genes Cdkn1a and Cdkn1b, as well as of genes encoding WNT antagonists, Frzb and Shisa3, to increase pro-proliferative WNT signaling. Despite these important molecular insights, we still lack knowledge of the DNA occupancy of TBX2 in the genome, and of the protein interaction partners involved in transcriptional repression of target genes. Methods We used chromatin immunoprecipitation (ChIP)-sequencing and expression analyses to identify genomic DNA-binding sites and transcription units directly regulated by TBX2 in the developing lung. Moreover, we purified TBX2 containing protein complexes from embryonic lung tissue and identified potential interaction partners by subsequent liquid chromatography/mass spectrometry. The interaction with candidate proteins was validated by immunofluorescence, proximity ligation and individual co-immunoprecipitation analyses. Results We identified Il33 and Ccn4 as additional direct target genes of TBX2 in the pulmonary mesenchyme. Analyzing TBX2 occupancy data unveiled the enrichment of five consensus sequences, three of which match T-box binding elements. The remaining two correspond to a high mobility group (HMG)-box and a homeobox consensus sequence motif. We found and validated binding of TBX2 to the HMG-box transcription factor HMGB2 and the homeobox transcription factor PBX1, to the heterochromatin protein CBX3, and to various members of the nucleosome remodeling and deacetylase (NuRD) chromatin remodeling complex including HDAC1, HDAC2 and CHD4. Conclusion Our data suggest that TBX2 interacts with homeobox and HMG-box transcription factors as well as with the NuRD chromatin remodeling complex to repress transcription of anti-proliferative genes in the pulmonary mesenchyme.

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TBX2 and TBX3 act downstream of canonical WNT signaling in patterning and differentiation of the mouse ureteric mesenchyme

Cited by 35 publications

References 69 publications

Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling

Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling

Single-Cell Epigenomics and Functional Fine-Mapping of Atherosclerosis GWAS Loci

Combined genomic and proteomic approaches reveal DNA binding sites and interaction partners of TBX2 in the developing lung

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