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Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE145931 | GEO | 2021/08/03

REPOSITORIES: GEO

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Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells [mTEC_bulk_RNAseq]

Project description:Thymic epithelial cells (TEC) guide selection of a T-cell repertoire that is reactive to pathogens but tolerant to self. While this process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire by TEC, the extent to which these cells reproduce peripheral isoform structures is unknown. We performed a transcriptomic investigation of transcript structures and splicing factor expression in medullary TEC and 21 peripheral tissues. Our results indicate that TEC re-use a small number of peripheral splicing factors to recreate a limited subset of the peripheral splice isoform repertoire. We found, for example, that TEC lacked both neuronal microexons and the splicing factor, Srrm4, which promotes their inclusion. We demonstrate a functional role for the Rbfox splicing factors in promoting medullary TEC development and the alternative splicing of promiscuously expressed genes. Our findings have implications for understanding autoimmune diseases and the development of antigen-specific immunotherapies.

2021-08-03 | GSE145930 | GEO

Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells [mTEC_ONT_RNAseq]

2021-08-03 | GSE145914 | GEO

Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells [Rbfox_SKO_RNAseq]

2021-08-03 | GSE145913 | GEO

Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells

Project description:Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells

| PRJNA608751 | ENA

Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells [mTEC_bulk_RNAseq]

Project description:Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells [mTEC_bulk_RNAseq]

| PRJNA608750 | ENA

Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells [mTEC_ONT_RNAseq]

Project description:Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells [mTEC_ONT_RNAseq]

| PRJNA608717 | ENA

Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells [Rbfox_SKO_RNAseq]

Project description:Rbfox contributes to a conservative program of self-antigen splicing in thymic epithelial cells [Rbfox_SKO_RNAseq]

| PRJNA608718 | ENA

Splicing Activation by Rbfox Requires Self-Aggregation through Its Tyrosine-Rich Domain.

Project description:Proteins of the Rbfox family act with a complex of proteins called the Large Assembly of Splicing Regulators (LASR). We find that Rbfox interacts with LASR via its C-terminal domain (CTD), and this domain is essential for its splicing activity. In addition to LASR recruitment, a low-complexity (LC) sequence within the CTD contains repeated tyrosines that mediate higher-order assembly of Rbfox/LASR and are required for splicing activation by Rbfox. This sequence spontaneously aggregates in solution to form fibrous structures and hydrogels, suggesting an assembly similar to the insoluble cellular inclusions formed by FUS and other proteins in neurologic disease. Unlike the pathological aggregates, we find that assembly of the Rbfox CTD plays an essential role in its normal splicing function. Rather than simple recruitment of individual regulators to a target exon, alternative splicing choices also depend on the higher-order assembly of these regulators within the nucleus.

| S-EPMC5553710 | biostudies-literature

Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity.

Project description:Promiscuous expression of numerous tissue-restricted self-antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential to safeguard self-tolerance. A distinct feature of promiscuous gene expression is its mosaic pattern (i.e., at a given time, each self-antigen is expressed only in 1-3% of mTECs). How this mosaic pattern is generated at the single-cell level is currently not understood. Here, we show that subsets of human mTECs expressing a particular TRA coexpress distinct sets of genes. We identified three coexpression groups comprising overlapping and complementary gene sets, which preferentially mapped to certain chromosomes and intrachromosomal gene clusters. Coexpressed gene loci tended to colocalize to the same nuclear subdomain. The TRA subsets aligned along progressive differentiation stages within the mature mTEC subset and, in vitro, interconverted along this sequence. Our data suggest that single mTECs shift through distinct gene pools, thus scanning a sizeable fraction of the overall repertoire of promiscuously expressed self-antigens. These findings have implications for the temporal and spatial (re)presentation of self-antigens in the medulla in the context of tolerance induction.

| S-EPMC3773787 | biostudies-literature

Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance.

Project description:The roles of autoimmune regulator (Aire) in the expression of the diverse arrays of tissue-restricted antigen (TRA) genes from thymic epithelial cells in the medulla (medullary thymic epithelial cells [mTECs]) and in organization of the thymic microenvironment are enigmatic. We approached this issue by creating a mouse strain in which the coding sequence of green fluorescent protein (GFP) was inserted into the Aire locus in a manner allowing concomitant disruption of functional Aire protein expression. We found that Aire(+) (i.e., GFP(+)) mTECs were the major cell types responsible for the expression of Aire-dependent TRA genes such as insulin 2 and salivary protein 1, whereas Aire-independent TRA genes such as C-reactive protein and glutamate decarboxylase 67 were expressed from both Aire(+) and Aire(-) mTECs. Remarkably, absence of Aire from mTECs caused morphological changes together with altered distribution of mTECs committed to Aire expression. Furthermore, we found that the numbers of mTECs that express involucrin, a marker for terminal epidermal differentiation, were reduced in Aire-deficient mouse thymus, which was associated with nearly an absence of Hassall's corpuscle-like structures in the medulla. Our results suggest that Aire controls the differentiation program of mTECs, thereby organizing the global mTEC integrity that enables TRA expression from terminally differentiated mTECs in the thymic microenvironment.

| S-EPMC2585853 | biostudies-literature

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