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Genomic binding and regulation of gene expression by the thyroid carcinoma-associated PAX8-PPARG fusion protein

ABSTRACT: A chromosomal translocation results in production of an oncogenic PAX8-PPARG fusion protein (PPFP) in a subset of thyroid carcinomas. PAX8 is an important thyroid transcription factor, and PPARG is a transcription factor that plays important roles in the biology of adipocytes and macrophages, but has no known function in the thyroid. PPFP retains the DNA binding domains of both proteins. However, the genomic DNA binding sites of PPFP have not been identified, and only limited data exist to characterize gene expression in PPFP thyroid carcinomas. Therefore, we expressed PPFP in PCCL3 rat thyroid cells and used ChIP-seq to identify PPFP genomic binding sites (PPFP peaks) and RNA-seq to characterize PPFP-dependent gene expression. The genome contains ~20 000 PPFP peaks, including known PAX8 and PPARG binding sites, indicating that both DNA binding domains are functional. PPFP binds to and regulates many genes involved in cancer-related processes such as development and cell division. PPFP also binds to and regulates many genes related to mitochondria and lipid metabolism that are regulated by PPARG in adipocytes. Our data highlight the complexity of PPFP as a transcription factor and the numerous ways that it regulates thyroid oncogenesis.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE70354 | GEO | 2016/01/21

SECONDARY ACCESSION(S): PRJNA288400

REPOSITORIES: GEO

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Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer [seq]

Project description:PAX8-PPARG fusion protein (PPFP) results from a t(2;3)(q13;p25) chromosomal translocation, is found in 30% of follicular thyroid carcinomas, and demonstrates oncogenic capacity in transgenic mice. A PPARG ligand, pioglitazone, is highly therapeutic in mice with PPFP thyroid cancer. However, only limited data exist to characterize the binding sites and oncogenic function of PPFP, or to explain the observed therapeutic effect of pioglitazone. Here we used our previously characterized transgenic mouse model of PPFP follicular thyroid carcinoma to identify PPFP binding sites in vivo using ChIP-seq, and to distinguish genes and pathways regulated directly or indirectly by PPFP with and without pioglitazone treatment via integration with RNA-seq data. PPFP bound to DNA regions containing the PAX8 and/or the PPARG motif, near genes involved in lipid metabolism, the cell cycle, apoptosis, and cell motility; the binding site distribution was highly concordant with our previous study in a rat PCCL3 cell line. Most strikingly, pioglitazone induced an immune cell infiltration including macrophages and T cells only in the presence of PPFP, which may be central to its therapeutic effect.

2016-12-21 | GSE85648 | GEO

Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas

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Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer [array]

Project description:PAX8-PPARG fusion protein (PPFP) results from a t(2;3)(q13;p25) chromosomal translocation, is found in 30% of follicular thyroid carcinomas, and demonstrates oncogenic capacity in transgenic mice. A PPARG ligand, pioglitazone, is highly therapeutic in mice with PPFP thyroid carcinoma. We used our previously characterized transgenic mouse model of PPFP thyroid carcinoma to identify PPFP binding sites in vivo using ChIP-seq, and to identify genes and pathways regulated by PPFP with and without pioglitazone treatment via integration with RNA-seq and Affymetrix microarray data. This submission contains the Affymetrix microarray data. PPFP and pioglitazone regulated genes involved in lipid and fatty acid metabolism, ribosome function, immune processes, cell death and other cancer-related processes. The RNA-seq data yielded similar findings.

2016-12-21 | GSE85583 | GEO

Human thyroid adenomas, carcinomas, and normals

Project description:Human samples of various thyroid carcinomas, adenomas, and normals, each from a different patient, had mRNA assays performed using Affymetrix HG_U133A arrays, with 22283 probe-sets. The 99 samples consisted of 4 normals, 10 follicular adenomas, 13 follicular carcinomas, 7 oncocytic adenomas, 8 oncocytic carcinomas, 51 papillary carcinomas (each typed as having classical, follicular or tall cell morphology), 4 anaplastic carcinomas, and 2 medullary carcinomas. Interesting additional information on common mutations are provided including RAS mutation, BRAF mutation, RET/PTC rearrangements, and PAX8/PPARG translocations. Details of those assays are provided in our linked publications, as well as additional details on the specific mutations in a few special cases. No survival data is provided. Information for 93 of the 99 samples was previously made available on the web. The anaplastic and medullary carcinoma data were not previously shared. A supplementary Excel spreadsheet holding the same processed data as the series matrix file is provided and is more compact. The raw (.CEL) files are also provided. Human samples of various thyroid carcinomas, adenomas, and normals. The 99 samples consisted of 4 normals, 10 follicular adenomas, 13 follicular carcinomas, 7 oncocytic adenomas, 8 oncocytic carcinomas, 51 papillary carcinomas (each typed as having classical, follicular or tall cell morphology), 4 anaplastic carcinomas, and 2 medullary carcinomas. Additional information on common mutations are provided including RAS mutation, BRAF mutation, RET/PTC rearrangements, and PAX8/PPARG translocations.

2011-02-09 | E-GEOD-27155 | biostudies-arrayexpress

Genome wide profiling of PAX8 binding stes in PCCL3 rat cells

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PAX8 transcriptional profiling in rat PCCL3 cells

Project description:PAX8 transcriptional profiling of rat PCCL3 cells comparing wild type cells with PAX8 silenced cells and scramble treated with PAX8 silenced cells

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Molecular regulation of PPARγ/RXRα signaling by the novel cofactor ZFP407

Project description:Cofactors interacting with PPARγ can regulate adipogenesis and adipocyte metabolism by modulating the transcriptional activity and selectivity of PPARγ signaling. ZFP407 was previously demonstrated to regulate PPARγ target genes such as GLUT4, and its overexpression improved glucose homeostasis in mice. Here, using a series of molecular assays, including protein-interaction studies, mutagenesis, and ChIP-seq, ZFP407 was found to interact with the PPARγ/RXRα protein complex in the nucleus of adipocytes. Consistent with this observation, ZFP407 ChIP-seq peaks significantly overlapped with PPARγ ChIP-seq peaks, with more than half of ZFP407 peaks overlapping with PPARγ peaks. Transcription factor binding motifs enriched in these overlapping sites included CTCF, RARα/RXRγ, TP73, and ELK1, which regulate cellular development and function within adipocytes. Site-directed mutagenesis of frequent PPARγ phosphorylation or SUMOylation sites did not prevent its regulation by ZFP407, while mutagenesis of ZFP407 domains potentially necessary for RXR and PPARγ binding abrogated any impact of ZFP407 on PPARγ activity. These data suggest that ZFP407 controls the activity of PPARγ, but does so independently of post-translational modifications, likely by direct binding, establishing ZFP407 as a newly identified PPARγ cofactor. In addition, ZFP407 ChIP-seq analyses identified regions that did not overlap with PPARγ peaks. These non-overlapping peaks were significantly enriched for the transcription factor binding motifs of TBX19, PAX8, HSF4, and ZKSCAN3, which may contribute to the PPARγ-independent functions of ZFP407 in adipocytes and other cell types.

2024-02-27 | GSE245861 | GEO

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