SOX transcription factors direct TCF-independent WNT/β-catenin responsive transcription to govern cell fate in human pluripotent stem cells

Mukherjee, Shreyasi; Luedeke, David M.; McCoy, Leslie F.; Iwafuchi-Doi, Makiko; Zorn, Aaron M.

doi:10.1016/j.celrep.2022.111247

Cited by 30 publications

(17 citation statements)

References 101 publications

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“…Solid arrows are interactions taken from the Drosophila timer gene network in Figure 8A; dotted arrows are two additional interactions that might be present in sequentially segmenting species. The arrow from Wg to Cad supposes that Wg signalling from a posterior signalling centre activates cad expression, even in the presence of D. [Note that both Sox and Zic transcription factors can have different regulatory effects in the presence or absence of Wnt signalling, via molecular interactions with β -catenin and TCF (Pourebrahim et al, 2011; Murgan et al, 2015; Mukherjee et al, 2022)]. The arrow from Cad to Opa completes an “AC-DC circuit” network motif (Panovska-Griffiths et al, 2013; Perez-Carrasco et al, 2018) between the timer genes.…”

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confidence: 99%

A timer gene network is spatially regulated by the terminal system in theDrosophilaembryo

Clark

Battistara

Benton

2022

Preprint

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In insects, patterning of the anteroposterior axis relies on exquisite coordination of segmentation gene expression in space and time. And yet, there is also wide variation across species in the timing of segmentation and the geometry of the embryonic fate map. The majority of described species exhibit sequential segmentation during posterior growth. Other species, such as the fly Drosophila melanogaster, specify almost all of their segments simultaneously prior to gastrulation. The dynamics of both sequential segmentation and simultaneous segmentation correlate with the spatiotemporal expression of the "timer" genes caudal, Dichaete and odd-paired, which are expressed sequentially within segmenting tissues. These genes have critical roles in the development of many species; however, even in the extensively studied Drosophila embryo, the regulatory interactions responsible for shaping their expression remain poorly understood. In particular, it is not known whether the timer genes cross-regulate each other, nor why they are differentially expressed between the broad region of the blastoderm that gives rise to the gnathal, thoracic and abdominal segments and the small posterior region that gives rise to the embryonic terminalia. In this work, we investigated these questions using multiplexed fluorescent in situ hybridisation and high resolution confocal imaging of wild-type and mutant Drosophila embryos. First, we re-examined segmentation gene expression in the posterior of the embryo, and discovered that two parasegment-like boundaries are generated sequentially from the terminal region during germband extension and posterior growth. Next, we found that caudal, Dichaete, and odd-paired dynamically cross-regulate each other, and also that they are differentially spatially regulated by the posterior terminal genes. Finally, we formalised the regulatory network we inferred from our data as a logical computational model. Our model qualitatively recapitulated both wild-type development and the mutant phenotypes we had examined. Our findings resolve a decades-long ambiguity over the number of segments formed during Drosophila embryogenesis. In addition, they reveal how dynamic spatial inputs from an extrinsic signalling centre modulate the intrinsic dynamics of a gene regulatory network to generate an essential developmental pattern.

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confidence: 99%

A timer gene network is spatially regulated by the terminal system in theDrosophilaembryo

Clark

Battistara

Benton

2022

Preprint

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“…APC mutation in the intestine played an essential role in the progression of CRA [ 21 ]. Wnt/β-catenin is closely related to stemness and promotes tumor proliferation via regulation of stem genes [ 22 ]. KEGG analysis of up-regulated genes showed Wnt/β-catenin had already enriched in CRA.…”

Section: Resultsmentioning

confidence: 99%

Identification and clinical validation of key genes as the potential biomarkers in colorectal adenoma

et al. 2023

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Background Colorectal cancer (CRC), ranking third in cancer prevalence and second in mortality worldwide, is mainly derived from colorectal adenoma (CRA). CRA is a common benign disease in the intestine with rapidly increasing incidence and malignant potential. Therefore, this study aimed to recognize significant biomarkers and original pathogenesis in CRA. Methods Transcriptome data of GSE8671, GSE37364, and GSE15960 were downloaded from the Gene Expression Omnibus (GEO) datasets, and differentially expressed genes (DEGs) were screened. Functional pathways enrichment, protein–protein interaction (PPI) network, stem-correlation analysis, CIBERSORT, risk score and survival analyses were performed. RT-qPCR and immunohistochemical staining were applied to verify our results. Results Screening for significant DEGs in each dataset, we identified 230 robust DEGs, including 127 upregulated and 103 downregulated genes. Functional pathways enrichment showed that these DEGs were distinctly enriched in various tumor-associated pathways, such as growth factor activity, extracellular structure organization, neutrophil activation, and inflammatory response. We filtered out two hub genes via STRING and Modules analysis, including CA2 and HSD11B2. Stem-correlation analysis displayed that hub genes were negatively associated with stem-related genes (Olfm4, CD44, CCND1 and MYC). The CIBERSORT algorithm indicated that Macrophage2, activated mast cells, and Neutrophils promoted CRA progression through inflammation. Survival analysis showed that CA2 and HSD11B2 were positively associated with survival outcomes in CRC. Conclusion Our study has successfully identified the critical role of two core genes in the development and oncogenesis of CRA, which provides novel insight into the underlying pathogenesis, potential biomarkers and therapeutic targets.

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“…Enormous efforts have been dedicated to unraveling the complexity of the response to Wnt/β-catenin signaling activation and deciphering the mechanisms that drive its remarkable tissue-specificity 45 . This included the identification of the different components of the Wnt/β-catenin transcriptional complex [46][47][48][49] and recently the varying patterns of β-catenin genome-wide binding in a time and context specific manner 27,[50][51][52][53] . However, the impact of Wnt/β-catenin activation on the 3D genome structure and its potential role in modulating the Wnt-dependent transcriptional output, is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Wnt signaling alters CTCF binding patterns and global chromatin structure

Nordin,

Chakraborty,

Jonasson

et al. 2024

Preprint

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Wnt signaling plays a pivotal role during development, stem cell maintenance, and tissue homeostasis. Upon Wnt pathway activation, β-catenin translocates to the nucleus where it binds the TCF/LEF transcription factors to drive the context-specific expression of Wnt target genes. Coordinating gene expression programs in vertebrates requires a complex interplay between the regulatory and the 3D organization of the genome. However, the impact of Wnt signaling on genome structure has been poorly explored. Here we investigated how Wnt signaling activation influences the binding patterns of CTCF, one of the core architectural proteins that helps establish the 3D genome organization be demarcating topologically associated domains (TAD). This study uncovered a series of CTCF rearrangements under Wnt, that we termed RUW. Notably, RUW sites that were gained upon Wnt activation were typically dependent on β-catenin and were characterized by both CTCF and TCF/LEF binding. Accordingly, many CTCF RUWs aligned with β-catenin binding patterns, and β-catenin and CTCF co-localized in vivo in discreet nuclear puncta only up-on pathway activation. Genome-wide investigation of CTCF-mediated 3D genomic interactions upon Wnt pathway stimulation supported the role of the identified RUWs in mediating Wnt-dependent chromatin loops. Lastly, targeted disruption of selected CTCF binding sites demonstrated their functional contribution to Wnt target gene regulation, implicating regulation of the 3D genomic structure in the execution of tran-scriptional programs orchestrated by developmental pathways.

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SOX transcription factors direct TCF-independent WNT/β-catenin responsive transcription to govern cell fate in human pluripotent stem cells

Cited by 30 publications

References 101 publications

A timer gene network is spatially regulated by the terminal system in theDrosophilaembryo

A timer gene network is spatially regulated by the terminal system in theDrosophilaembryo

Identification and clinical validation of key genes as the potential biomarkers in colorectal adenoma

Wnt signaling alters CTCF binding patterns and global chromatin structure

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