Dataset Information

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 thyroid carcinomas. PAX8 is a thyroid transcription factor, and PPARG is a transcription factor that plays important roles in adipocytes and macrophages. PPFP retains the DNA binding domains of both proteins; however, the genomic binding sites of PPFP have not been identified, and only limited data exist to characterize gene expression in PPFP thyroid carcinomas. Therefore, the oncogenic function of PPFP is poorly understood. 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. PPFP peaks (~20,000) include known PAX8 and PPARG binding sites and are enriched with both motifs, indicating that both DNA binding domains are functional. PPFP binds to and regulates many genes involved in cancer-related processes. In PCCL3 thyroid cells, PPFP binds to adipocyte PPARG target genes in preference to macrophage PPARG target genes, consistent with the pro-adipogenic nature of PPFP and its ligand pioglitazone in thyroid cells. PPFP induces oxidative stress in thyroid cells, and pioglitazone increases susceptibility to further oxidative stress. Our data highlight the complexity of PPFP as a transcription factor and the numerous ways that it regulates thyroid oncogenesis.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4747342 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Zhang Yanxiao Y Yu Jingcheng J Lee Chee C Xu Bin B Sartor Maureen A MA Koenig Ronald J RJ

Oncotarget 20151201 38

A chromosomal translocation results in production of an oncogenic PAX8-PPARG fusion protein (PPFP) in thyroid carcinomas. PAX8 is a thyroid transcription factor, and PPARG is a transcription factor that plays important roles in adipocytes and macrophages. PPFP retains the DNA binding domains of both proteins; however, the genomic binding sites of PPFP have not been identified, and only limited data exist to characterize gene expression in PPFP thyroid carcinomas. Therefore, the oncogenic functio ...[more]

PMID: 26595524

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Project description:The transcription factor Pax8 is essential for the differentiation of thyroid cells. However, there are few data on genes transcriptionally regulated by Pax8 other than thyroid-related genes. To better understand the role of Pax8 in the biology of thyroid cells, we obtained transcriptional profiles of Pax8-silenced PCCl3 thyroid cells using whole genome expression arrays and integrated these signals with global cis-regulatory sequencing studies performed by ChIP-Seq analysisExhaustive analysis of Pax8 immunoprecipitated peaks demonstrated preferential binding to intragenic regions and CpG-enriched islands, which suggests a role of Pax8 in transcriptional regulation of orphan CpG regions. In addition, ChIP-Seq allowed us to identify Pax8 partners, including proteins involved in tertiary DNA structure (CTCF) and chromatin remodeling (Sp1), and these direct transcriptional interactions were confirmed in vivo. Moreover, both factors modulate Pax8-dependent transcriptional activation of the sodium iodide symporter (Nis) gene promoter. We ultimately combined putative and novel Pax8 binding sites with actual target gene expression regulation to define Pax8-dependent genes. Functional classification suggests that Pax8-regulated genes may be directly involved in important processes of thyroid cell function such as cell proliferation and differentiation, apoptosis, cell polarity, motion and adhesion, and a plethora of DNA/protein-related processes.Our study provides novel insights into the role of Pax8 in thyroid biology, exerted through transcriptional regulation of important genes involved in critical thyrocyte processes. In addition, we found new transcriptional partners of Pax8, which functionally cooperate with Pax8 in the regulation of thyroid gene transcription. Besides, our data demonstrate preferential location of Pax8 in non-promoter CpG regions. These data point to an orphan CpG island-mediated mechanism that represents a novel role of Pax8 in the transcriptional output of the thyrocyte.

Dataset Information

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

Publications

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

Similar Datasets

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