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Differential features of Aire-induced and Aire-independent promiscuous gene expression in thymic epithelial cells

ABSTRACT: Promiscuous gene expression (pGE) of numerous self-antigens in thymic epithelial cells (TEC) enables the elimination of self-reactive T cells. The autoimmune regulator (Aire) is the only known molecular determinant driving pGE in the thymus but the existence of Aire-independent mechanisms has been inferred. Here, we analyzed the poly(A)+ transcriptome of TEC populations by RNA-sequencing (RNA-seq) in order to reveal differential features of Aire-induced vs. –independent pGE. We report an unanticipated effect of Aire deletion on the proliferation and differentiation of cortical TEC. Moreover, the RNA-seq data reveal the breath of Aire-induced and –independent pGE in medullary TEC (mTEC) subsets and the extent of thymic peripheral tissue representation. The results suggest that Aire-induced promiscuously expressed transcripts affect several functions with far reaching biological consequences in mTEC. High-throughput characterization of TEC transcriptomes will enable progress in understanding TEC biology and the establishment of self-tolerance.

ORGANISM(S): Mus musculus

PROVIDER: GSE65617 | GEO | 2015/05/19

SECONDARY ACCESSION(S): PRJNA274486

REPOSITORIES: GEO

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Differential features of Aire-induced and Aire-independent promiscuous gene expression in thymic epithelial cells

Project description:Promiscuous gene expression (pGE) of numerous self-antigens in thymic epithelial cells (TEC) enables the elimination of self-reactive T cells. The autoimmune regulator (Aire) is the only known molecular determinant driving pGE in the thymus but the existence of Aire-independent mechanisms has been inferred. Here, we analyzed the poly(A)+ transcriptome of TEC populations by RNA-sequencing (RNA-seq) in order to reveal differential features of Aire-induced vs. –independent pGE. We report an unanticipated effect of Aire deletion on the proliferation and differentiation of cortical TEC. Moreover, the RNA-seq data reveal the breath of Aire-induced and –independent pGE in medullary TEC (mTEC) subsets and the extent of thymic peripheral tissue representation. The results suggest that Aire-induced promiscuously expressed transcripts affect several functions with far reaching biological consequences in mTEC. High-throughput characterization of TEC transcriptomes will enable progress in understanding TEC biology and the establishment of self-tolerance. The mRNA profiles of cTEC, mTEClo and mTEChi from 6-8 week-old wild type (WT) and Aire-/- (KO) mice were generated by RNA-sequencing using Illumina HiSeq2000.

2015-05-19 | E-GEOD-65617 | biostudies-arrayexpress

Comprehensively profiling the chromatin architecture of tissue restricted antigen expression in thymic epithelial cells

Project description:Thymic epithelial cells (TEC) effect crucial roles in thymopoiesis including the control of negative thymocyte selection. This process depends on their capacity to express promiscuously genes encoding tissue-restricted antigens. This competence is accomplished in medullary TEC (mTEC) in part by the presence of the transcriptional facilitator AutoImmune REgulator, AIRE. AIRE-regulated gene transcription is marked by repressive chromatin modifications, including H3K27me3. When during TEC development these chromatin marks are established, however, remains unclear. Here we use a comprehensive ChIP-seq dataset of multiple chromatin modifications in different TEC subtypes to demonstrate that the chromatin landscape is established early in TEC differentiation. Much of the chromatin architecture found in mature mTEC was found to be present already over earlier stages of mTEC lineage differentiation. This was reflected by the fact that a machine learning approach accurately classified genes as AIRE-induced or AIRE-independent both in immature and mature mTEC. Moreover, analysis of TEC specific enhancer elements identified candidate transcription factors likely to be important in mTEC development and function. Our findings indicate that the mature mTEC chromatin landscape is laid down early in mTEC differentiation, and that AIRE is not required for large-scale re-patterning of chromatin in mTEC.

2018-08-28 | GSE114713 | GEO

RNA-seq of medullary thymic epithelial cell (mTEC) subsets in inducible Aire-lineage tracing mice

Project description:The goal of the study was to sequence mRNA expression from sorted medullary thymic epithelial cell (mTEC) subsets in inducible Aire-CreERT2.R26-Stopfl-tdTomato lineage tracing mice after a pulse chase. Four cell subsets were sorted 7 days after a single 2mg pulse of tamoxifen administered by oral gavage. 4 biological replicates (1,2,3,4) were collected derived from 12 pooled thymi per replicate. From the DAPI-;CD45-;EpCAM+ TEC pool, cells were sorted as: pre-Aire (MHCIIlo;RFP-), early-Aire (MHCIIhi;RFP-), late-Aire (MHCIIhi;RFP+), and post-Aire (MHCIIlo;RFP+). The data were used to identify differentially expressed genes across the four mTEC subsets to examine mTEC heterogeneity and identify novel mTEC subpopulations.

2018-05-19 | GSE114651 | GEO

The effect of the Autoimmune regulator (Aire) gene on microRNA transcriptional profile of 3.10 mTEC cell line

Project description:Medullary thymic epithelial cells (mTECs) contribute to self-tolerance through the ectopic expression of peripheral tissue antigens (PTAs) in the thymus. Autoimmune regulator (Aire) is to date the best characterized transcriptional regulator known to at least partially coordinate PTA expression in mTECs. Furthermore the expression of Aire-dependent and -independent genes is also modulated by microRNAs. Given the transcriptional regulation exerted by Aire in mTEC cells and the role of miRNAs in post-transcriptional control, we used a Mus musculus mTEC cell line (3.10) which constitutively express Aire in culture) to knockdown Aire gene by means of siRNA transfection and then observe the effect of Aire knockdown in the transcriptional profile of miRNAs by means of oligomicroarrays. The Agilent oligomicroarrays were used to determine the large scale the miRNA transcriptional profiles of control or Aire-knockdown 3.10 mTECs.

2016-06-27 | E-MTAB-4596 | biostudies-arrayexpress

Aire regulates transfer of antigen from mTEC to dendritic cells for induction of thymic tolerance

Project description:To investigate the role of Aire in thymic selection, we examined the cellular requirements for generation of ovalbumin (OVA)-specific CD4 and CD8 T cells in mice expressing OVA under the control of the rat insulin promoter (RIP). Aire-deficiency reduced the number of mature single positive (SP) OVA-specific CD4+ or CD8+ T cells in the thymus, independent of OVA expression. Importantly, it also contributed in two way to OVA-dependent negative selection depending on the T cell type. Aire-dependent negative selection of OVA-specific CD8 T cells correlated with Aire-regulated expression of OVA. By contrast, for OVA-specific CD4 T cells, Aire affected tolerance induction by a mechanism that operated independent of the level of OVA expression, controlling access of antigen presenting cells to mTEC-expressed OVA. This study supports the view that one mechanism by which Aire controls thymic negative selection is by regulating the indirect presentation of mTEC-derived antigens by thymic dendritic cells. It also indicates that mTEC can mediate tolerance by direct presentation of Aireregulated antigens to both CD4 and CD8 T cells.

2011-04-06 | GSE28393 | GEO

Aire regulates transfer of antigen from mTEC to dendritic cells for induction of thymic tolerance

2011-04-06 | E-GEOD-28393 | biostudies-arrayexpress

The effect of the autoimmune regulator (Aire) gene on the transcriptional expression profile of 3.10 mTEC cell line.

Project description:Medullary thymic epithelial cells (mTECs) contribute to self-tolerance through the ectopic expression of peripheral tissue antigens (PTAs) in the thymus. PTA expression in mTECs is largely dependent on the autoimmune regulator (Aire) gene. Here we used a Mus musculus mTEC cell line (3.10 mTEC line, which constitutively express Aire in culture) to knockdown Aire gene by means of siRNA transfection. Aire knockdown was confirmed by means of qRT-PCR and RNA-FISH (for Aire mRNA levels), immunofluorescence and western blot (for AIRE protein levels).The Agilent oligo microarrays were used to determine the large scale transcriptional expression profiles of control or Aire-knockdown 3.10 mTECs.

2015-12-31 | E-MTAB-3879 | biostudies-arrayexpress

Expression data of Sirt1-deficient and sufficient medullary thymic epithelial cells (mTECs)

2015-05-25 | GSE68363 | GEO

Transcription profiling of thymic epithelial cells from C57BL/6 and AIRE knockout mice.

Project description:TEC (B6 vs Aire KO). Thymic epithelial cells from B6 strain and AIRE KO are compared.

2007-12-01 | E-GEOD-2515 | biostudies-arrayexpress

Expression data of Sirt1-deficient and sufficient medullary thymic epithelial cells (mTECs)

Project description:Medullary thymic epithelial cells play essential role for induction of central self-tolerance. This functional capacity is mediated through a phenomenon known as promiscuous gene expression (pGE) of various tissue-restricted antigen (TRA) genes. pGE was previously shown to be mediated by a single factor called the Autoimmune regulator (Aire), which is specically expressed by mTECs. The aim of this study was to analyze the impact of deacetylase Sirtuin1, which is also highly expressed by mTECs, on mTEC gene expression profile and compare it with the impact of Aire. We used Affymetrix mouse 1ST arrays to analyze the impact of the Sirt1 gene on the gene expression profile of MHC-II high medullary thymic epithelial cells Mature MHC-II high mTECs were flow-sorted from thymi isolated from B6.Sirt1fl/fl, B6.Sirt1fl/flFoxn1-Cre and B6.Aire–/– 6weeks old mice. Typically, 3 mice were pooled to obtain 30-60 thousand sorted mTECs, which were then analyzed by gene expression profiling. Specifically, total RNA was extracted from ~30,000 pooled sorted cells using Trizol. Purified total RNA was then amplified using the MessageAmp RNA kit (Ambion). Biotinylated cRNA was then hybridized to Affymetrix Mouse Gene 1-ST arrays by the genomics core at the Weizmann Institute

2015-05-25 | E-GEOD-68363 | biostudies-arrayexpress

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