Similar Datasets
Project description:The Activating Protein 2β transcription factor (TFAP2B; AP-2β) is a marker for both lobular and molecular apocrine/HER2-E breast cancers, despite these tumours having very different prognoses. We show that simultaneous expression of both AP-2β and the estrogen receptor (ESR1, ER) marks well differentiated, low proliferation cells that are characteristic of luminal A lobular tumours, but loss of ER expression occurs when the tumour cells progress to molecular apocrine tumours. To discover potential explanations for this behaviour we performed chromatin immunoprecipitation sequencing (ChIP-seq) for AP-2β, AR, GATA3, FOXA1 and H3K27 acetylation in ER-negative MDA-MB-453 breast cancer cells. We find that all four transcription factors frequently bind to the same enhancers and that these enhancers are more likely to be active when AP-2β is present. Molecular apocrine genes are significantly more likely to have enhancers bound to all four transcription factors flanked by H3K27 acetylation. When AP-2β binds separately from the other factors, it binds close to the transcription start site, where it shows very high enrichment for H3K27 acetylation. AP-2 family proteins activate transcription by recruiting CITED proteins and p300/CBP. Since AR, FOXA1 and GATA3 are themselves able to recruit histone acetyl-transferases, we infer that AP-2β regulates the activity of those histone acetyl-transferases. We propose that this broad fundamental role in transcription explains the contradictory functions, both oncogenic and tumour suppressing, that have been assigned to AP-2 family members in previous studies on cancer.
2023-12-31 | GSE207472 | GEO
Project description:The Activating Protein 2β transcription factor (TFAP2B; AP-2β) is a marker for both lobular and molecular apocrine/HER2-E breast cancers, despite these tumours having very different prognoses. We show that simultaneous expression of both AP-2β and the estrogen receptor (ESR1, ER) marks well differentiated, low proliferation cells that are characteristic of luminal A lobular tumours, but loss of ER expression occurs when the tumour cells progress to molecular apocrine tumours. To discover potential explanations for this behaviour we performed chromatin immunoprecipitation sequencing (ChIP-seq) for AP-2β, AR, GATA3, FOXA1 and H3K27 acetylation in ER-negative MDA-MB-453 breast cancer cells. We find that all four transcription factors frequently bind to the same enhancers and that these enhancers are more likely to be active when AP-2β is present. Molecular apocrine genes are significantly more likely to have enhancers bound to all four transcription factors flanked by H3K27 acetylation. When AP-2β binds separately from the other factors, it binds close to the transcription start site, where it shows very high enrichment for H3K27 acetylation. AP-2 family proteins activate transcription by recruiting CITED proteins and p300/CBP. Since AR, FOXA1 and GATA3 are themselves able to recruit histone acetyl-transferases, we infer that AP-2β regulates the activity of those histone acetyl-transferases. We propose that this broad fundamental role in transcription explains the contradictory functions, both oncogenic and tumour suppressing, that have been assigned to AP-2 family members in previous studies on cancer.
2023-12-31 | GSE207230 | GEO
Project description:The evolution of a hinged moveable jaw with variable morphology is considered a major factor behind the successful expansion of the vertebrates. DLX homeobox transcription factors are crucial for establishing the positional code that patterns the mandible, maxilla and intervening hinge domain, but how the genes encoding these proteins are regulated remains unclear. Herein, we demonstrate that the concerted action of the AP-2α and AP-2β transcription factors within the mouse neural crest is essential for jaw patterning. In the absence of these two proteins, the hinge domain is lost and there are alterations in the size and patterning of the jaws correlating with dysregulation of homeobox gene expression, with reduced levels of Emx, Msx and Dlx paralogs accompanied by an expansion of Six1 expression. Moreover, detailed analysis of morphological features and gene expression changes indicate significant overlap with various compound Dlx gene mutants. Together, these findings reveal that the AP-2 genes have a major function in mammalian neural crest development, influencing patterning of the craniofacial skeleton via the DLX code, an effect that has implications for vertebrate facial evolution, as well as for human craniofacial disorders.
| S-EPMC5825845 | biostudies-literature
Project description:Molecular subtyping of cancer offers tremendous promise for the optimization of a precision oncology approach to anticancer therapy. Recent advances in pancreatic cancer research uncovered various molecular subtypes with tumors expressing a squamous/basal-like gene expression signature displaying a worse prognosis. Through unbiased epigenome mapping, we identified deltaNp63 as a major driver of a gene signature in pancreatic cancer cell lines, which we report to faithfully represent the highly aggressive pancreatic squamous subtype observed in vivo, and display the specific epigenetic marking of genes associated with decreased survival. Importantly, depletion of deltaNp63 in these systems significantly decreased cell proliferation and gene expression patterns associated with a squamous subtype and transcriptionally mimicked a subtype switch. Using genomic localization data of deltaNp63 in pancreatic cancer cell lines coupled with epigenome mapping data from patient-derived xenografts, we uncovered that deltaNp63 mainly exerts its effects by activating subtype-specific super enhancers. Furthermore, we identified a group of 45 subtype-specific super enhancers that are associated with poorer prognosis and are highly dependent on deltaNp63. Genes associated with these enhancers included a network of transcription factors, including HIF1A, BHLHE40, and RXRA, which form a highly intertwined transcriptional regulatory network with deltaNp63 to further activate downstream genes associated with poor survival.
| S-EPMC6310858 | biostudies-literature
Project description:The molecular mechanism regulating sleep largely remains to be elucidated. In humans, families that carry mutations in TFAP2B, which encodes the transcription factor AP-2β, self-reported sleep abnormalities such as short-sleep and parasomnia. Notably, AP-2 transcription factors play essential roles in sleep regulation in the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster Thus, AP-2 transcription factors might have a conserved role in sleep regulation across the animal phyla. However, direct evidence supporting the involvement of TFAP2B in mammalian sleep was lacking. In this study, by using the CRISPR/Cas9 technology, we generated two Tfap2b mutant mouse strains, Tfap2bK144 and Tfap2bK145 , each harboring a single-nucleotide mutation within the introns of Tfap2b mimicking the mutations in two human kindreds that self-reported sleep abnormalities. The effects of these mutations were compared with those of a Tfap2b knockout allele (Tfap2b-). The protein expression level of TFAP2B in the embryonic brain was reduced to about half in Tfap2b+/- mice and was further reduced in Tfap2b-/- mice. By contrast, the protein expression level was normal in Tfap2bK145/+ mice but was reduced in Tfap2bK145/K145 mice to a similar extent as Tfap2b-/- mice. Tfap2bK144/+ and Tfap2bK144/K144 showed normal protein expression levels. Tfap2b+/- female mice showed increased wakefulness time and decreased nonrapid eye movement sleep (NREMS) time. By contrast, Tfap2bK145/+ female mice showed an apparently normal amount of sleep but instead exhibited fragmented NREMS, whereas Tfap2bK144/+ male mice showed reduced NREMS time specifically in the dark phase. Finally, in the adult brain, Tfap2b-LacZ expression was detected in the superior colliculus, locus coeruleus, cerebellum, and the nucleus of solitary tract. These findings provide direct evidence that TFAP2B influences NREMS amounts in mice and also show that different mutations in Tfap2b can lead to diverse effects on sleep architecture.
| S-EPMC7648583 | biostudies-literature
Project description:The developmental mechanisms that orchestrate differentiation of specific nephron segments are incompletely understood, and the factors that maintain their terminal differentiation after nephrogenesis remain largely unknown. Here, the transcription factor AP-2β is shown to be required for the differentiation of distal tubule precursors into early stage distal convoluted tubules (DCTs) during nephrogenesis. In contrast, its downstream target KCTD1 is essential for terminal differentiation of early stage DCTs into mature DCTs, and impairment of their terminal differentiation owing to lack of KCTD1 leads to a severe salt-losing tubulopathy. Moreover, sustained KCTD1 activity in the adult maintains mature DCTs in this terminally differentiated state and prevents renal fibrosis by repressing β-catenin activity, whereas KCTD1 deficiency leads to severe renal fibrosis. Thus, the AP-2β/KCTD1 axis links a developmental pathway in the nephron to the induction and maintenance of terminal differentiation of DCTs that actively prevents their de-differentiation in the adult and protects against renal fibrosis.
| S-EPMC7497565 | biostudies-literature
Project description:Transcription factors AP-2α and AP-2β have been suggested to regulate the differentiation of nephron precursor populations towards distal nephron segments. Here, we show that in the adult mammalian kidney AP-2α is found in medullary collecting ducts, whereas AP-2β is found in distal nephron segments except for medullary collecting ducts. Inactivation of AP-2α in nephron progenitor cells does not affect mammalian nephrogenesis, whereas its inactivation in collecting ducts leads to defects in medullary collecting ducts in the adult. Heterozygosity for AP-2β in nephron progenitor cells leads to progressive distal convoluted tubule abnormalities and β-catenin/mTOR hyperactivation that is associated with renal fibrosis and cysts. Complete loss of AP-2β in nephron progenitor cells caused an absence of distal convoluted tubules, renal cysts, and fibrosis with β-catenin/mTOR hyperactivation, and early postnatal death. Thus, AP-2α and AP-2β have non-redundant distinct spatiotemporal functions in separate segments of the distal nephron in the mammalian kidney.
| S-EPMC9038906 | biostudies-literature
Project description:Chromatin plays a central role in eukaryotic gene regulation. We performed genome-wide mapping of epigenetically marked nucleosomes to determine their position both near transcription start sites and at distal regulatory elements, including enhancers. In prostate cancer cells, where androgen receptor binds primarily to enhancers, we found that androgen treatment dismisses a central nucleosome present at androgen receptor binding sites that is flanked by a pair of marked nucleosomes. A new quantitative model built on the behavior of such nucleosome pairs correctly identified regions bound by the regulators of the immediate androgen response, including androgen receptor and FOXA1. More importantly, this model also correctly predicted previously unidentified binding sites for other transcription factors present after prolonged androgen stimulation, including OCT1 and NKX3-1. Therefore, quantitative modeling of enhancer structure provides a powerful predictive method to infer the identity of transcription factors involved in cellular responses to specific stimuli.
| S-EPMC2932437 | biostudies-literature
Project description:Parathyroid hormone-related protein (PTHrP) regulates cell fate and specifies the mammary mesenchyme during embryonic development. Loss of PTHrP or its receptor (Pthr1) abolishes the expression of mammary mesenchyme markers and allows mammary bud cells to revert to an epidermal fate. By contrast, overexpression of PTHrP in basal keratinocytes induces inappropriate differentiation of the ventral epidermis into nipple-like skin and is accompanied by ectopic expression of Lef1, β-catenin and other markers of the mammary mesenchyme. In this study, we document that PTHrP modulates Wnt/β-catenin signaling in the mammary mesenchyme using a Wnt signaling reporter, TOPGAL-C. Reporter expression is completely abolished by loss of PTHrP signaling and ectopic reporter activity is induced by overexpression of PTHrP. We also demonstrate that loss of Lef1, a key component of the Wnt pathway, attenuates the PTHrP-induced abnormal differentiation of the ventral skin. To characterize further the contribution of canonical Wnt signaling to embryonic mammary development, we deleted β-catenin specifically in the mammary mesenchyme. Loss of mesenchymal β-catenin abolished expression of the TOPGAL-C reporter and resulted in mammary buds with reduced expression of mammary mesenchyme markers and impaired sexual dimorphism. It also prevented the ectopic, ventral expression of mammary mesenchyme markers caused by overexpression of PTHrP in basal keratinocytes. Therefore, we conclude that a mesenchymal, canonical Wnt pathway mediates the PTHrP-dependent specification of the mammary mesenchyme.
| S-EPMC3478689 | biostudies-literature
Project description:We generated 6 transgenic lines with insertion of an expression plasmid for the R883/M xanthine dehydrogenase (XDH) mutant protein. Approximately 20% of the animals deriving from one of the transgenic lines show ocular abnormalities and an increase in intra-ocular pressure which are consistent with glaucoma. The observed pathologic phenotype is not due to expression of the transgene, but rather the consequence of the transgene insertion site, which has been defined by genome sequencing. The insertion site maps to chromosome 1qA3 in close proximity to the loci encoding AP-2β and AP-2δ, two proteins expressed in the eye. The insertion leads to a reduction in AP-2β and AP-2δ levels. Down-regulation of AP-2β expression is likely to be responsible for the pathologic phenotype, as conditional deletion of the Tfap2b gene in the neural crest has recently been shown to cause defective development of the eye anterior segment and early-onset glaucoma. In these conditional knock-out and our transgenic mice, the morphological/histological features of the glaucomatous pathology are surprisingly similar. Our transgenic mouse represents a model of angle-closure glaucoma and a useful tool for the study of the pathogenesis and the development of innovative therapeutic strategies.
| S-EPMC5593953 | biostudies-literature