Chromatin Regulation by TFAP2A
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA695515 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13571556.fastq.gz | Fastqsanger.gz | |||
| SRR13571557.fastq.gz | Fastqsanger.gz | |||
| SRR13571558.fastq.gz | Fastqsanger.gz | |||
| SRR13571559.fastq.gz | Fastqsanger.gz | |||
| SRR18220801_1.fastq.gz | Fastqsanger.gz |
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Project description:We have deleted TFAP2A and its redundantly-acting paralog TFAP2C in human melanoma SkMel28 cell lines and are assessing MITF binding using Cleavage Under Targets and Release Using Nuclease (CUT&RUN). Conversely, we deleted all copies of MITF in SkMEL28 cells and are similarly profiling TFAP2A bound loci. We predict TFAP2A functions as a pioneer factor for MITF during melanocyte development and that in the absence of TFAP2A, MITF binding at loci normally co-bound by MITF/TFAP2A will be disrupted.
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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.
2017-02-17 | GSE72953 | GEO
Project description:Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the “master regulator” of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.
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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
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Project description:The Aryl Hydrocarbon Receptor (AHR) is an environmental sensor and an indispensable regulator of epithelial homeostasis. To investigate AHR-mediated gene regulation, we performed a comprehensive transcriptomic and epigenomic analysis using human primary epidermal keratinocytes. Our results showed that AHR activation led to the induction of canonical transcription factors involved in epidermal differentiation as an early response, i.e. Transcription Factor AP-2α (TFAP2A), while epidermal differentiation-related genes, such as filaggrin and keratins, were activated as late responsive genes. The identified AHR-TFAP2A axis and its role in keratinocyte terminal differentiation was confirmed through AHR and TFAP2A knockout using CRISPR/Cas9. Our findings demonstrate that AHR regulates epidermal differentiation through the transient activation of specific transcription factors, such as TFAP2A, in response to environmental cues. The herein identified AHR-TFAP2A axis provides a promising target for the treatment of diseases related to skin barrier dysfunction.
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Project description:In developing melanocytes and in melanoma cells, multiple paralogs of the Activating-enhancer-binding Protein 2 family of transcription factors (TFAP2) contribute to expression of genes encoding pigmentation regulators, but their interaction with Microphthalmia transcription factor (MITF), a master regulator of these cells, is unclear. Supporting the model that Tfap2 facilitates MITF's ability to activate expression of pigmentation genes, single-cell seq analysis of zebrafish embryos revealed that pigmentation genes are only expressed in the subset of mitfa-expressing cells that also express Tfap2 paralogs. To test this model in SK-MEL-28 melanoma cells we deleted the two TFAP2 paralogs with highest expression, TFAP2A and TFAP2C, creating TFAP2 knockout (TFAP2-KO) cells. We then assessed gene expression, chromatin accessibility, binding of TFAP2A and of MITF, and the chromatin marks H3K27Ac and H3K27Me3 which are characteristic of active enhancers and silenced chromatin, respectively. Integrated analyses of these datasets indicate TFAP2 paralogs directly activate enhancers near genes enriched for roles in pigmentation and proliferation, and directly repress enhancers near genes enriched for roles in cell adhesion. Consistently, compared to WT cells, TFAP2-KO cells proliferate less and adhere to one another more. TFAP2 paralogs and MITF co-operatively activate a subset of enhancers, with the latter necessary for MITF binding and chromatin accessibility. By contrast, TFAP2 paralogs and MITF do not appear to co-operatively inhibit enhancers. These studies reveal a mechanism by which TFAP2 profoundly influences the set of genes activated by MITF, and thereby the phenotype of pigment cells and melanoma cells.
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Project description:Neo/null loss of Tfap2a in E10.5 mouse facial prominences
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Project description:The Aryl Hydrocarbon Receptor (AHR) is an environmental sensor and an indispensable regulator of epithelial homeostasis. To investigate AHR-mediated gene regulation, we performed a comprehensive transcriptomic and epigenomic analysis using human primary epidermal keratinocytes. Our results showed that AHR activation led to the induction of canonical transcription factors involved in epidermal differentiation as an early response, i.e. Transcription Factor AP-2α (TFAP2A), while epidermal differentiation-related genes, such as filaggrin and keratins, were activated as late responsive genes. The identified AHR-TFAP2A axis and its role in keratinocyte terminal differentiation was confirmed through AHR and TFAP2A knockout using CRISPR/Cas9. Our findings demonstrate that AHR regulates epidermal differentiation through the transient activation of specific transcription factors, such as TFAP2A, in response to environmental cues. The herein identified AHR-TFAP2A axis provides a promising target for the treatment of diseases related to skin barrier dysfunction.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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