Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer
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Yanxiao Zhang1,4, Jingcheng Yu2, Vladimir Grachtchouk2, Tingting Qin1, Carey N. Lumeng3, Maureen A. Sartor1, Ronald J. Koenig2
1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA
2Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
3Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA
4Current address: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA
Ronald J. Koenig, email: email@example.com
Keywords: peroxisome proliferator-activated receptor gamma, follicular thyroid cancer, pioglitazone, differentiation, gene fusion
Received: August 25, 2016 Accepted: December 13, 2016 Published: December 20, 2016
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.
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