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.
Highlights
A chromosomal translocation fusing the genes PAX8 and PPARG is found in 30% of follicular thyroid carcinomas [1]
PPARG fusion protein (PPFP) contains the DNA binding domains (DBDs) of both PAX8 and PPARG, and we found that both are functional in vivo, with 62% of peaks containing a PAX8 motif and/or a PPARG motif (Figure 2A)
The PAX8-PPARG gene fusion is a consequence of a t(2;3)(q13;p25) chromosomal translocation and leads to production of a PAX8-PPARG fusion protein, PPFP [1]
Summary
A chromosomal translocation fusing the genes PAX8 and PPARG is found in 30% of follicular thyroid carcinomas [1]. PAX8 is a member of the paired box family of transcription factors. It is required for normal thyroid development and in the mature thyroid, it induces the expression of thyroid-specific genes [2, 3]. PPARG is a member of the nuclear receptor family of transcription factors. It is expressed at very low levels in the normal thyroid and has no known function in that organ. PPFP contains all but the very carboxyl terminal section of PAX8 fused to the entirety of PPARG1. PPFP contains both the PAX8 and the PPARG DNA binding domains (DBDs), and PPARG ligands function as PPFP ligands
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