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TFAP2A orchestrates gene regulatory networks and tubular architecture in kidney outer medullary collecting ducts.

ABSTRACT: Mutations of the transcription factor TFAP2A are associated with congenital anomalies of the kidney and urinary tract in humans. In mice, deficiency of its ortholog Tfap2a in collecting duct cells causes widened epithelial tubules in the outer medulla of the adult kidney, but the molecular mechanisms of this phenotype are unknown. In this study, we identified gene regulatory networks controlled by Tfap2a in mouse kidney collecting ducts by combining gene knockout and transcriptomics. Integrated analyses of single-nucleus and bulk RNA-sequencing data from kidneys of adult Tfap2a knockout and control mice indicated deregulated expression of genes associated with cell adhesion and Wnt signaling pathways. Validation studies revealed that Tfap2a controls Wnt9b and Alcam, known regulators of kidney tubule morphogenesis. Our data provide novel insights into kidney epithelial gene regulatory networks controlled by Tfap2a and its potential functional role in congenital renal disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE290794 | GEO | 2025/08/08

REPOSITORIES: GEO

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TFAP2A orchestrates gene regulatory networks and tubular architecture in kidney outer medullary collecting ducts [bulk RNA-seq]

Project description:Mutations of the transcription factor TFAP2A are associated with congenital anomalies of the kidney and urinary tract in humans. In mice, deficiency of its ortholog Tfap2a in collecting duct cells causes widened epithelial tubules in the outer medulla of the adult kidney, but the molecular mechanisms of this phenotype are unknown. In this study, we identified gene regulatory networks controlled by Tfap2a in mouse kidney collecting ducts by combining gene knockout and transcriptomics. Integrated analyses of single-nucleus and bulk RNA-sequencing data from kidneys of adult Tfap2a knockout and control mice indicated deregulated expression of genes associated with cell adhesion and Wnt signaling pathways. Validation studies revealed that Tfap2a controls Wnt9b and Alcam, known regulators of kidney tubule morphogenesis. Our data provide novel insights into kidney epithelial gene regulatory networks controlled by Tfap2a and its potential functional role in congenital renal disease.

2025-08-08 | GSE282959 | GEO

Gene expression profile of zebrafish renal collecting ducts

2012-08-24 | GSE32363 | GEO

Gene expression profile of zebrafish renal collecting ducts

Project description:The kidney is the main hematopoietic organ in teleost fish. Various stages of hematopoietic cells were observed in the interstitial tissue of the kidney. We recently demonstrated that zebrafish hematopoietic stem cells (HSCs) expressing jam1a were specifically localized along the renal collecting ducts in the adult kidney. Interestingly, most of HSCs invaded into the intracellular spaces of the epithelium in collecting ducts, suggesting that collecting ducts provide a specific microenvironment for HSCs. In order to identify niche factors in collecting ducts, we performed microarray analysis in collecting ducts isolated from the Tg(jam1a:EGFP) zebrafish kidney. Collecting ducts were isolated from Tg(jam1a:EGFP) zebrafish under a fluorescent microscope. To examine the effect of X-ray irradiation on the niche, collecting ducts were isolated from the fish irradiated with 25Gy. The whole kidney tissues were also used for a comparison analysis. Two independent replicates consisting of five zebrafish were prepared for each sample.

2012-08-24 | E-GEOD-32363 | biostudies-arrayexpress

TFAP2A supports HIF-1-dependent activation of hypoxia-inducible genes

Project description:Hypoxia can be established under pathological conditions, such as cancer, due to the imbalance between oxygen supply and consumption. Hypoxia Inducible Transcription Factor HIF-1 mediates the physiological response to hypoxia but also regulates multiple steps of carcinogenesis. Despite its well-defined oxygen-dependent activation, many aspects of HIF-1 transcriptional activity as well as interaction with chromatin remain elusive. We have recently shown that TFAP2A physically interacts with HIF-1 and hypoxia-dependent deSUMOylation of TFAP2A positively affects HIF-1 activity. We now present ChIP-seq analysis showing that TFAP2A resides together with HIF-1α on the promoters of a subset of hypoxia-regulated genes, the mRNA expression of which is downregulated by silencing of TFAP2A. Interestingly, CRISPR-mediated knockdown of TFAP2A expression under hypoxia decreased the occupancy of HIF-1α on these promoters and affected chromatin accessibility. Mechanistically, we reveal that the Ku70/Ku80 protein complex interacts with TFAP2A in a SUMO-dependent manner under hypoxia and participates in HIF-dependent gene expression. Moreover, using stable expression of TFAP2A forms that either lack or constitutively carry a SUMO modification, we could show that SUMOylation affects binding of TFAP2A to chromatin. Overall, our data suggest that TFAP2A is an important co-regulator of the HIF-1-dependent transcriptional response to hypoxia and SUMOylation fine-tunes this regulation. As both TFAP2A and HIF-1 play critical roles in cancer progression, a detailed characterization of their crosstalk could lead to novel therapeutic strategies for targeting and killing cancer cells in hypoxic tumors.

2025-05-23 | PXD053747 | Pride

Tfap2a dependnt cha

Project description:Neo/null loss of Tfap2a in E10.5 mouse facial prominences triplicate run comparing tissue dissected from the nasal, maxillary and mandibular comparing AP-2 mutant and control embryos

2014-08-05 | E-GEOD-60058 | biostudies-arrayexpress

Disruption of the TFAP2A regulatory domain causes Branchio-Oculo-Facial Syndrome (BOFS) and illuminates pathomechanisms for other human neurocristopathies [scRNA-seq]

Project description:BOFS is a rare congenital syndrome that arises due to defects during neural crest (NC) development and is thus considered as a human neurocristopathy. All reported BOFS cases are caused by heterozygous mutations within TFAP2A. Here we describe a unique BOFS patient carrying a de novo heterozygous inversion in which one of the breakpoints is located 40 kb downstream of TFAP2A. Using in vitro and in vivo NC developmental models, we uncovered that TFAP2A is located within a large Topologically Associating Domain (TAD) containing enhancers essential for TFAP2A expression in NC cells (NCC). Importantly, using patient-specific hiPSC lines, we showed that the inversion causes a loss of physical interactions between the inverted TFAP2A allele and its cognate enhancers, leading to TFAP2A monoallelic and haploinsufficient expression in human NCC. More generally, our results highlight potential etiological mechanisms for other human neurocristopathies and illustrate how TAD disruption can lead to a loss of enhancer gene-interactions and, consequently, to pathological changes in gene expression.

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Disruption of the TFAP2A regulatory domain causes Branchio-Oculo-Facial Syndrome (BOFS) and illuminates pathomechanisms for other human neurocristopathies [ChIP-seq]

2018-11-01 | GSE108518 | GEO

Disruption of the TFAP2A regulatory domain causes Branchio-Oculo-Facial Syndrome (BOFS) and illuminates pathomechanisms for other human neurocristopathies [ATAC-seq]

2018-11-01 | GSE108517 | GEO

Identification of down-stream targets of Notch signaling within the developing mosue kidney collecting ducts.

Project description:Notch signaling deficient kidney collecting ducts may serve as a useful resource to identify principal cell lineage and intercalated lineage specific factors since they develop a reduced number of principal cells and an increased number of intercalated cells compared with wild type kidney collecting ducts. We compared RNA from three E18.5 mouse kidneys per group: HoxB7Cre;RBPJf/-;Rosa+/Eyfp (Notch signaling deficient; mutant) versus RBPJf/f;Rosa+/Eyfp (wild type).

2017-02-27 | GSE68389 | GEO

TFAP2A ChIP-seq in mouse immortalized melanocytes

Project description:Damage to the gene regulatory network governing terminal differentiation of melanocytes leads to pigmentation phenotypes and increases the risk for melanoma. Microphthalmia-associated transcription factor (MITF) directly activates expression of melanocyte differentiation effectors, and levels of MITF have been proposed to govern the melanoma phenotype. Mutations in the gene encoding Transcription Factor Activator Protein 2 alpha (TFAP2A) cause reduced pigmentation in model organisms and premature hair graying in humans, and TFAP2A expression tends to be lower in advanced melanoma tumors than in benign nevi. However, the transcriptional targets of TFAP2A in melanocytes, and the epistatic relationship of TFAP2A and MITF, have been unclear. Using microarray-based analysis of zebrafish tfap2a mutant embryos, we generated a profile of genes whose expression is Tfap2a-dependent. We conducted anti-TFAP2A chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) in immortalized mouse melanocytes and human primary melanocytes, and discovered that TFAP2A peaks are present near the promoters of Tfap2a-dependent genes expressed in melanocytes, and also at the majority of enhancers active in melanocytes. Comparison of TFAP2A ChIP-seq data to published MITF ChIP-seq data showed that the set of genes with promoters bound by both MITF and TFAP2A is enriched for the gene ontology term “pigment cell differentiation.” Deletion analysis of one such co-bound promoter, for Transient Receptor Potential Melastatin-like 1(TRPM1), confirmed that its expression depends on the presence of MITF binding sites as previously shown, but also depends on the presence of TFAP2A binding sites. Finally, we find that mitfa and tfap2a interact genetically in zebrafish. Collectively, these results show that TFAP2A, operating in parallel with MITF, directly regulates effectors of terminal differentiation in melanocytes and melanoma.

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