Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues

ABSTRACT: Endogenous retroelements (ERE) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer. Despite evidence that some EREs can be expressed at the RNA and protein levels in specific contexts, a systems-level evaluation of their expression in human tissues is lacking. We report that all human tissues express EREs but the breadth and magnitude of ERE expression are very heterogeneous from one tissue to another. ERE expression was particularly high in two MHC-I-deficient tissues (ESCs and testis) and one MHC-I-expressing tissue, mTECs. In mutant mice, we report that the exceptional expression of EREs in mTECs was AIRE-independent. MS analyses identified 103 non-redundant ERE-derived MAPs (ereMAPs) in B-LCLs. These ereMAPs preferentially derived from sense translation of intronic EREs. Notably, detailed analyses of their amino acid composition revealed that ERE-derived MAPs presented homology to viral MAPs. This study shows that ERE expression in somatic tissues is more pervasive and heterogeneous than anticipated. The high and diversified expression of EREs in mTECs and their ability to generate MAPs suggest that EREs may play an important role in the establishment of self-tolerance. The viral-like properties of ERE-derived MAPs suggest that those not expressed in mTECs can be highly immunogenic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147570 | GEO | 2020/04/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

LC-MSMS of OVCAR-3 class I immunopeptidome

Project description:Endogenous retroelements (ERE) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer. Despite evidence that some EREs can be expressed at the RNA and protein levels in specific contexts, a systems-level evaluation of their expression in human tissues is lacking. We report that all human tissues express EREs but the breadth and magnitude of ERE expression are very heterogeneous from one tissue to another. ERE expression was particularly high in two MHC-I-deficient tissues (ESCs and testis) and one MHC-I-expressing tissue, mTECs. In mutant mice, we report that the exceptional expression of EREs in mTECs was AIRE-independent. MS analyses identified 103 non-redundant ERE-derived MAPs (ereMAPs) in B-LCLs. These ereMAPs preferentially derived from sense translation of intronic EREs. Notably, detailed analyses of their amino acid composition revealed that ERE-derived MAPs presented homology to viral MAPs. This study shows that ERE expression in somatic tissues is more pervasive and heterogeneous than anticipated. The high and diversified expression of EREs in mTECs and their ability to generate MAPs suggest that EREs may play an important role in the establishment of self-tolerance. The viral-like properties of ERE-derived MAPs suggest that those not expressed in mTECs can be highly immunogenic.

2020-05-26 | PXD018124 | Pride

LC-MSMS of the MHC-I immunopeptidome of AML cell line, THP-1

Project description:The hypomethylating agent 5-azacytidine (AZA) is the first-line induction therapy for AML patients unsuitable for intensive chemotherapy. The anti-tumor effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, clear evidence supporting higher ERE MAPs presentation after AZA treatment in AML is lacking. Interestingly, we find that AZA-mediated DNMT2 inhibition leads to autophagy induction, which is responsible for mitigating ERE MAPs generation. To validate our findings, we examined the immunopeptidome of THP-1 cells treated with AZA combined with autophagy inhibitor, Spautin-1 or decitabine (DAC, non-DNMT2 inhibiting HMA) through a proteogenomic approach.

2024-04-17 | PXD046853 | Pride

LC-MSMS of the MHC-I immunopeptidome of AML cell lines

Project description:The hypomethylating agent 5-azacytidine (AZA) is the first-line induction therapy for AML patients unsuitable for intensive chemotherapy. The anti-tumor effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, clear evidence supporting higher ERE MAPs presentation after AZA treatment in AML is lacking. Therefore, we examined the immunopeptidome of four AML cell lines treated with AZA through a proteogenomic approach to validate this hypothesis.

2024-04-17 | PXD038663 | Pride

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

Project description:Reverse transcription-derived sequences account for at least half of the human genome. Although these retroelements are formidable motors of evolution, they can occasionally cause disease, and accordingly are inactivated during early embryogenesis through epigenetic mechanisms. In the mouse, at least for endogenous retroviruses, important mediators of this process are the tetrapod-specific KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor TRIM28. The present study demonstrates that KRAB/TRIM28-mediated regulation is responsible for controlling a very broad range of human-specific endogenous retroelements (EREs) in human embryonic stem (ES) cells and that it exerts, as a consequence, a marked effect on the transcriptional dynamics of these cells. It further reveals reciprocal dependence between TRIM28 recruitment at specific families of EREs and DNA methylation. It finally points to the importance of persistent TRIM28-mediated control of ERE transcriptional impact beyond their presumed inactivation by DNA methylation. Analyses of epigentic effectors and marks in KAP1 WT and KD human embryonic stem cells

2014-05-29 | E-GEOD-57989 | biostudies-arrayexpress

ChIP-exo and ChIP-seq of human KRAB-ZNFs transduced in HEK 293T cells

Project description:Kruppel-associated box (KRAB)-containing zinc-finger proteins (KZFPs) represent the largest family of transcription factors encoded by higher vertebrates. Together with their heterochromatin-inducing cofactor KAP1, many act as repressors of endogenous retroelements (EREs) during early embryonic genome reprogramming, yet their widespread expression in adult tissues and enrichment at other genetic loci indicate additional roles. By characterizing the protein interactome of 101 of the ~350 human KZFPs, we uncovered that it is highly diversified for a subset of those. Most of placental mammal- or primate-restricted KZFPs, which primarily bind EREs and constitute 90% of human KZFPs, essentially recruit KAP1 and effectors. However, certain KZFPs conserved in placental mammals and more distant clades associated with factors related to functions such as genome architecture or RNA processing. Additionally, members of the most conserved human KZFPs did not appear to interact with KAP1. Nevertheless, KZFPs from coelacanth, our most distant KZFP-encoding relative, bind KAP1 from this species. We thus propose that KZFPs first emerged as ERE-controlling repressors, had their pool continuously renewed by turn-over of their hosts’ ERE loads, thereby yielded largely species-specific sets of transcriptional controllers, yet occasionally produced derivatives that escaped this evolutionary flushing by development of novel functions and exaptation.

2019-08-12 | GSE120539 | GEO

Transcriptome diversity in human medullary thymic epithelial cells - RNAseq

Project description:The induction of central T-cell tolerance in the thymus depends on the presentation of peripheral self-epitopes by medullary thymic epithelial cells (mTECs), enabled by a process known as promiscuous gene expression (pGE). Transcriptome diversity generated during pGE has many contributors, including non-canonical transcription initiation, alternative splicing and expression of endogenous retroelements (EREs). However, their significance and regulation are poorly understood in the healthy human thymus. Here, we mapped the expression of genome-wide transcripts in immature and mature human mTECs using high-throughput 5'Cap and RNA sequencing. Overall, 96\% of protein coding genes were represented across five human mTEC samples, with mature mTECs showing increased rates of global transcript mis-initiation. Both mTEC populations have increased splicing entropy, which appears to be driven by expression of peripheral splicing factors. Furthermore, EREs enriched in long terminal repeat retrotransposons are up-regulated during mTEC maturation and enriched in genomic proximity to differentially expressed genes. We provide an interactive interface to explore the transcriptome diversity we uncovered at http://transcriptomediversity.cshl.edu/. Our findings represent an important first step towards the generation of a comprehensive map of transcriptome diversity in the healthy human thymus. Ultimately, a complete map of thymic expression diversity will allow for the identification of epitopes that contribute to the pathogenesis of auto-immunity and that drive immune recognition of tumor antigens.

2022-04-30 | GSE201719 | GEO

Transcriptome diversity in human medullary thymic epithelial cells - 5'Cap sequencing

Project description:The induction of central T-cell tolerance in the thymus depends on the presentation of peripheral self-epitopes by medullary thymic epithelial cells (mTECs), enabled by a process known as promiscuous gene expression (pGE). Transcriptome diversity generated during pGE has many contributors, including non-canonical transcription initiation, alternative splicing and expression of endogenous retroelements (EREs). However, their significance and regulation are poorly understood in the healthy human thymus. Here, we mapped the expression of genome-wide transcripts in immature and mature human mTECs using high-throughput 5'Cap and RNA sequencing. Overall, 96% of protein coding genes were represented across five human mTEC samples, with mature mTECs showing increased rates of global transcript mis-initiation. Both mTEC populations have increased splicing entropy, which appears to be driven by expression of peripheral splicing factors. Furthermore, EREs enriched in long terminal repeat retrotransposons are up-regulated during mTEC maturation and enriched in genomic proximity to differentially expressed genes. We provide an interactive interface to explore the transcriptome diversity we uncovered at http://transcriptomediversity.cshl.edu/. Our findings represent an important first step towards the generation of a comprehensive map of transcriptome diversity in the healthy human thymus. Ultimately, a complete map of thymic expression diversity will allow for the identification of epitopes that contribute to the pathogenesis of auto-immunity and that drive immune recognition of tumor antigens.

2022-04-30 | GSE201718 | GEO

Regulatory Sharing Between Estrogen Receptor α Bound Enhancers [ATAC-seq]

Project description:The human genome encodes an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by the combined action of multiple enhancers. We have previously shown that neighboring estrogen-responsive enhancers, which are approximately 5,000 basepairs apart, exhibit complex synergistic contributions to the production of an estrogenic transcriptional response. Here we sought to determine the molecular underpinnings of the observed enhancer cooperativity. We generated genetic deletions of individual estrogen receptor  (ER) bound enhancers and found that enhancers containing full estrogen response element (ERE) motifs control ER binding at neighboring sites, while enhancers with pre-existing histone acetylation/accessibility confer a permissible chromatin environment to the neighboring enhancers. Genome engineering revealed that a cluster of two enhancers with half EREs could not compensate for the lack of a full ERE site within the cluster. In contrast, two enhancers with full EREs produced a transcriptional response greater than the wild-type locus. By swapping genomic sequences between enhancers, we found that the genomic location in which a full ERE resides strongly influences enhancer activity. Our results lead to a model in which a full ERE is required for ER recruitment, but the presence of pre-existing histone acetylation within an enhancer cluster is also needed in order for estrogen-driven gene regulation to occur.

2020-03-18 | GSE147140 | GEO

Regulatory Sharing Between Estrogen Receptor α Bound Enhancers [ChIP-seq]

2020-03-18 | GSE147141 | GEO

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

2014-05-29 | GSE57989 | GEO