title: Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer.
abstract: 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.
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.|Current address: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Yanxiao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Grachtchouk
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Carey N
authors.initials: CN
authors.lastname: Lumeng
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Koenig
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000072636:PAX8 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D047495:PPAR gamma; D011993:Recombinant Fusion Proteins; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: differentiation; follicular thyroid cancer; gene fusion; peroxisome proliferator-activated receptor gamma; pioglitazone