LINE1 are spliced in non-canonical transcript variants to regulate T cell quiescence and exhaustion

Marasca, Federica; Sinha, Shruti; Vadalà, Rebecca; Polimeni, Benedetto; Ranzani, Valeria; Paraboschi, Elvezia Maria; Burattin, Filippo Vittorio; Ghilotti, Marco; Crosti, Mariacristina; Negri, Maria Luce; Campagnoli, Susanna; Notarbartolo, Samuele; Sartore‐Bianchi, Andrea; Siena, Salvatore; Prati, Daniele; Montini, Giovanni; Viale, Giuseppe; Torre, Olga; Harari, Sergio; Grifantini, Renata; Soldà, Giulia; Biffo, Stefano; Abrignani, Sergio; Bodega, Beatrice

doi:10.1038/s41588-021-00989-7

Cited by 48 publications

(55 citation statements)

References 56 publications

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“…These cis regulatory element-derived RNAs (CRE-derived RNAs) are likely a mixture of enhancer RNAs (eRNAs) and promoter upstream RNAs 65,66 . Another subset of RNAs mostly overlapped or were immediately downstream of TEs (e.g., UTL69657), in agreement with prior studies showing that TEs are a source of RNAs that associate with chromatin 11,25,12 . A fourth and fifth category of UTLs did not have any of the above features but were either antisense to known genes or localized in intergenic regions.…”

Section: A Highly Cell-state Specific Population Of Unannotated Rnas ...supporting

confidence: 89%

Global mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions

Limouse

Smith

Jukam

et al. 2022

Preprint

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Non-coding RNAs (ncRNAs) are transcribed throughout the genome and provide regulatory inputs to gene expression through their interaction with chromatin. The genomic targets and regulatory mechanisms of most ncRNAs remain unknown. Using chromatin-associated RNA sequencing (ChAR-seq) we obtained a global map of RNA-chromatin interactions, transcriptome and genome-wide, in human embryonic stem cells and definitive endoderm. We defined the overall architecture of the RNA-chromatin interactome that encompasses all long non-coding RNAs, intronic RNAs, as well as unannotated RNAs derived from regulatory elements, transposable elements, and intergenic regions. We show that the interactome is cell state specific, involves functionally diverse classes of RNAs, and can be accurately predicted by a simple model accounting for RNA expression and distance to their DNA targets. We show that nearly all ncRNAs exclusively interact with genes in close three-dimensional proximity to their transcription locus. We identified a small number of RNAs that deviate from that behavior and interact with many loci across the genome. By relating the changes in the interactome during differentiation to changes in gene expression, we demonstrate that activation or repression of individual genes is unlikely to be controlled by the activity of a single ncRNA.

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Section: A Highly Cell-state Specific Population Of Unannotated Rnas ...supporting

confidence: 89%

Global mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions

Limouse

Smith

Jukam

et al. 2022

Preprint

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“…Reduction in the number of LINE1-containing transcripts restores the effect function of T cells. Although LINE-1 is known to be upregulated in senescence cells, leading to a type 1 IFN response, it has been suggested that the level of LINE-1 expression is important for modulating T cell quiescence, effector function and exhaustion ( Marasca et al, 2022 ).…”

Section: Cellular Senescence In Immune Cellsmentioning

confidence: 99%

Immune Senescence, Immunosenescence and Aging

et al. 2022

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With aging, there is increased dysfunction of both innate and adaptive immune responses, which contributes to impaired immune responses to pathogens and greater mortality and morbidity. This age-related immune dysfunction is defined in general as immunosenescence and includes an increase in the number of memory T cells, loss of ability to respond to antigen and a lingering level of low-grade inflammation. However, certain features of immunosenescence are similar to cellular senescence, which is defined as the irreversible loss of proliferation in response to damage and stress. Importantly, senescence cells can develop an inflammatory senescence-associated secretory phenotype (SASP), that also drives non-autonomous cellular senescence and immune dysfunction. Interestingly, viral infection can increase the extent of immune senescence both directly and indirectly, leading to increased immune dysfunction and inflammation, especially in the elderly. This review focuses on age-related immune dysfunction, cellular senescence and the impaired immune response to pathogens.

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“…To evaluate the effects of depletion of L1 RNA aberrantly accumulated in the nucleus, we used L1-specific 2′F-ANA (2′-deoxy-2′-fluoro- d -arabinonucleic acid)–modified ASO (L1 ASO) to knock down L1 RNA ( 30 ). The 2′F-ANA modification in the oligonucleotide backbone improves both cell permeability and the stability of the oligonucleotides inside the cells compared to nonmodified ASOs ( 31 , 32 ).…”

Section: Resultsmentioning

confidence: 99%

LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes

et al. 2022

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Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here, we showed that LINE-1 ( Long Interspersed Nuclear Element-1; L1 ) RNA accumulation was an early event in both typical and atypical human progeroid syndromes. L1 RNA negatively regulated the enzymatic activity of the histone-lysine N -methyltransferase SUV39H1 (suppression of variegation 3-9 homolog 1), resulting in heterochromatin loss and onset of senescent phenotypes in vitro. Depletion of L1 RNA in dermal fibroblast cells from patients with different progeroid syndromes using specific antisense oligonucleotides (ASOs) restored heterochromatin histone 3 lysine 9 and histone 3 lysine 27 trimethylation marks, reversed DNA methylation age, and counteracted the expression of senescence-associated secretory phenotype genes such as p16 , p21 , activating transcription factor 3 ( ATF3 ), matrix metallopeptidase 13 ( MMP13 ), interleukin 1a ( IL1a ), BTG anti-proliferation factor 2 ( BTG2 ), and growth arrest and DNA damage inducible beta ( GADD45b ). Moreover, systemic delivery of ASOs rescued the histophysiology of tissues and increased the life span of a Hutchinson-Gilford progeria syndrome mouse model. Transcriptional profiling of human and mouse samples after L1 RNA depletion demonstrated that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response, and DNA damage were down-regulated. Our results highlight the role of L1 RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.

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LINE1 are spliced in non-canonical transcript variants to regulate T cell quiescence and exhaustion

Cited by 48 publications

References 56 publications

Global mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions

Global mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions

Immune Senescence, Immunosenescence and Aging

LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes

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