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As the name suggests, non-LTR retrotransposons lack the long terminal repeats characteristic of the LTR retrotransposons. Additionally, both LTR and non-LTR retrotransposons use distinct mechanisms of mobilization. Non-LTR retrotransposons are further divided into two classes - Long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), both of which occur abundantly in most mammals, including humans. Some of the active non-LTR retrotransposons in humans are L1...
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DNA-only transposons are called autonomous transposons since they code for the enzyme transposase that is required for the transposition mechanism. Insertion of transposons can alter gene functions in multiple ways. They can mutate the gene, alter gene expression by introducing a novel promoter or insulator sequence, introduce new splice sites, and change the mRNA transcripts produced, or remodel chromatin structure.
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Transposons make up a significant part of genomes of various organisms. Therefore, it is believed that transposition played a major evolutionary role in speciation by changing genome sizes and modifying gene expression patterns. For example, in bacteria, transposition can lead to conferring antibiotic resistance. Movement of transposable elements within the genetic pool of pathogenic bacteria can aid in transfer of antibiotic-resistant genetic elements. In eukaryotes, transposons can carry out...
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Transposons01:24

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Transposons, or "jumping genes," are small mobile genetic elements (MGEs) that range from 700 to 40,000 base pairs in length. They are found in all organisms and can move within the same chromosome or transfer to different chromosomes. In some cases, transposons can also jump between different host DNA molecules, such as plasmids or viruses, contributing to genetic variability.Barbara McClintock first discovered these mobile genetic elements in the 1940s while studying maize genetics, and she...
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LTR Retrotransposons03:08

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LTR retrotransposons are class I transposable elements with long terminal repeats flanking an internal coding region. These elements are less abundant in mammals compared to other class I transposable elements. About 8 percent of human genomic DNA comprises LTR retrotransposons. Some of the common examples of LTR retrotransposons are Ty elements in yeast and Copia elements in Drosophila.
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Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Epigenetically controlled tumor antigens derived from splice junctions between exons and transposable elements.

Marianne Burbage1, Ares Rocañín-Arjó1, Blandine Baudon1

  • 1Institut Curie, Université Paris Sciences et Lettres, 75005 Paris, France.

Science Immunology
|February 3, 2023
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Summary
This summary is machine-generated.

New tumor antigens arise from splicing between exons and transposable elements (TEs). These exon-TE junctions are immunogenic and can be targeted for cancer vaccines, showing promise for cancer therapy.

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Area of Science:

  • Oncology
  • Immunology
  • Epigenetics

Background:

  • Epigenetic alterations, including transposable element (TE) derepression and alternative splicing defects, are common in cancer.
  • Noncanonical splice junctions between exons and TEs are potential sources of tumor-specific antigens.

Purpose of the Study:

  • To investigate exon-TE splicing junctions as a source of tumor-specific antigens.
  • To assess the immunogenicity and therapeutic potential of peptides derived from these junctions.

Main Methods:

  • Analysis of mRNA junctions in normal and tumor tissues.
  • Immunopeptidome profiling of tumor cell lines.
  • In vivo vaccination studies in tumor-bearing mice.
  • Investigation of the role of Setdb1 in regulating exon-TE junctions.

Main Results:

  • Exon-TE splicing junctions are expressed in normal tissues and tumors, with some being tumor-specific.
  • Peptides derived from exon-TE junctions were identified on MHC-I molecules in tumor cells.
  • These peptides elicited immunogenic responses in mice and delayed tumor growth upon vaccination.
  • Inactivation of Setdb1 led to increased expression of immunogenic exon-TE junctions.

Conclusions:

  • Exon-TE splicing junctions represent epigenetically regulated, immunogenic tumor antigens in mice.
  • These findings open new avenues for tumor targeting and cancer vaccination strategies.