Unknown,Transcriptomics,Genomics,Proteomics

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Comparison of gene expression in thyrocytes between wildtype and thyroid-specific IFNg transgenic mice

ABSTRACT: Hürthle cells are found in thyroid tumors and autoimmunity, and have a unique appearance characterized by swollen eosinophilic cytoplasm filled with mitochondria and hyperchromatic nucleus. The pathogenesis of Hürthle cells remains unknown. We have generated transgenic mice expressing IFNg specifically in thyroid gland, and shown they develop changes in the thyroid follicular cell that resemble those of the human Hürthle cell. Transcriptome analysis by serial analysis of gene expression revealed an increased expression of immunoproteasome subunits in transgenic thyrocytes. LMP2, an immunoproteasome subunit also known as PSMB9 or ib1, provided critical for Hürthle cells and hypothyroidism development. Transgenic mice treated with a proteasome inhibitor ameliorated the Hürthle cell phenotype, and failed to develop it when crossed to LMP2 deficient mice. LMP2 was expressed in Hürthle cells from Hashimoto thyroiditis and thyroidal cancer patients. We propose that LMP2 is a nobel therapeuetic target for Hürthle cell lesions. We used 16 wildtype female mice for "Thyroid_wildtype_CD45depleted" and 3 thyroid specific IFNg transgenic female mice for "Thyroid_IFNg_transgenic_CD45depleted". Both wildtype and transgenic mouse thyroids have hematopoiteic cells, especially transgenic mouse have numerous mononuclear cell infiltration. We purely wanted to study gene expression of thyrocytes, because Hürthle cell is a follicular cell and a majority of thyrocytes are follicular cells. A difference of number of mice between two groups are due to a difference of size of thyroid lobes (Kimura et al. Int J Exp Pathol 86, 97-106, 2005).

ORGANISM(S): Mus musculus

SUBMITTER: Patrizio Caturegli

PROVIDER: E-GEOD-15114 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.

Kimura Hiroaki J HJ Chen Cindy Y CY Tzou Shey-Cherng SC Rocchi Roberto R Landek-Salgado Melissa A MA Suzuki Koichi K Kimura Miho M Rose Noel R NR Caturegli Patrizio P

PloS one 20091117 11

<h4>Background</h4>Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown.<h4>Methodology/principal findings</h4>Using transgenic mice chronically expressing IFNgamma in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysi ...[more]

PMID: 19924240

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Project description:Radiation is an established cause of thyroid cancer and growing evidence supports a role for H2O2 in spontaneous thyroid carcinogenesis. Little is known about the molecular programs activated by these agents in thyroid cells. We profiled the DNA damage response and cell death induced by M-NM-3-radiation (0.1M-bM-^@M-^S5Gy) and H2O2 (0.0025M-bM-^@M-^S0.3mM) in primary human thyroid cells and T-cells. While the two cell types had more comparable radiation responses, 3- to 10-fold more H2O2 was needed to induce detectable DNA damage in thyrocytes. At H2O2 and radiation doses incurring double-strand breaks (DSB), cell death occurred after 24hrs in T-cells, but not in thyrocytes. We next prepared thyroid and T-cells primary cultures from 8 donors operated for non-cancerous pathologies and profiled their genome-wide transcriptional response 4hr after: 1) exposure to 1 Gy radiation, 2) treatment with H2O2, or 3) no treatment. Two H2O2 doses were investigated, calibrated in each cell type as to elicit levels of single- and double-strand breaks equivalent to 1 Gy M-NM-3-radiation. The transcriptional responses of thyrocyte and T-cells to radiation were similar, involving DNA repair and cell death genes. In addition to this transcriptional program, H2O2 also upregulated antioxidant genes in thyrocytes, including glutathione peroxidases (GPx) at the DSB-inducing dose. By contrast, a transcriptional storm involving thousands of genes was raised in T-cells. Finally, we showed that GPx inhibition reduced the DNA damaging effect of H2O2 in thyrocytes. We conjecture that defects of anti- H2O2 protection could promote spontaneous thyroid cancers. Here we characterize the response of thyrocytes to H2O2 from the perspective of DNA damage (SSB and DSB), cell death and genome-wide transcription. We adopted a dual comparative set up. First, in order to gain preliminary insights about which effects are specific to thyrocytes, all experiments were run in parallel in T-cells. Second, all experiments were replicated with radiation, providing a comparison with a proven etiological agent of PTCs. Hence, we investigated all 4 combinations of two factors: thyrocytes vs. T-cells and H2O2 vs. radiation. Cell lines divide indefinitively owning to basic dysfunctions of cell cycle controls. These have the potential to distort the stress response, DNA repair and cell death in particular. Hence, we worked exclusively on human primary cultures. The radiation and presumably also the H2O2 responses vary among individuals. We seek to average out individual effects by replicating the microarray experiments across the matched T-cells and thyrocytes of 8 donors.

Dataset Information

Comparison of gene expression in thyrocytes between wildtype and thyroid-specific IFNg transgenic mice

Publications

Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.

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