How gene expression is controlled to preserve human T cell quiescence is poorly understood. Here we show that non-canonical splicing variants containing long interspersed nuclear element 1 (LINE1) enforce naive CD4(+) T cell quiescence. LINE1-containing transcripts are derived from CD4(+) T cell-specific genes upregulated during T cell activation. In naive CD4(+) T cells, LINE1-containing transcripts are regulated by the transcription factor IRF4 and kept at chromatin by nucleolin; these transcripts act in cis, hampering levels of histone 3 (H3) lysine 36 trimethyl (H3K36me3) and stalling gene expression. T cell activation induces LINE1-containing transcript downregulation by the splicing suppressor PTBP1 and promotes expression of the corresponding protein-coding genes by the elongating factor GTF2F1 through mTORC1. Dysfunctional T cells, exhausted in vitro or tumor-infiltrating lymphocytes (TILs), accumulate LINE1-containing transcripts at chromatin. Remarkably, depletion of LINE1-containing transcripts restores TIL effector function. Our study identifies a role for LINE1 elements in maintaining T cell quiescence and suggests that an abundance of LINE1-containing transcripts is critical for T cell effector function and exhaustion.Non-canonical transcripts containing LINE1 transposable elements maintain naive CD4(+) T cell quiescence and interfere with gene expression in cis. LINE1-containing transcripts are downregulated upon T cell activation.

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

Paraboschi, Elvezia Maria;Soldà, Giulia;
2022-01-01

Abstract

How gene expression is controlled to preserve human T cell quiescence is poorly understood. Here we show that non-canonical splicing variants containing long interspersed nuclear element 1 (LINE1) enforce naive CD4(+) T cell quiescence. LINE1-containing transcripts are derived from CD4(+) T cell-specific genes upregulated during T cell activation. In naive CD4(+) T cells, LINE1-containing transcripts are regulated by the transcription factor IRF4 and kept at chromatin by nucleolin; these transcripts act in cis, hampering levels of histone 3 (H3) lysine 36 trimethyl (H3K36me3) and stalling gene expression. T cell activation induces LINE1-containing transcript downregulation by the splicing suppressor PTBP1 and promotes expression of the corresponding protein-coding genes by the elongating factor GTF2F1 through mTORC1. Dysfunctional T cells, exhausted in vitro or tumor-infiltrating lymphocytes (TILs), accumulate LINE1-containing transcripts at chromatin. Remarkably, depletion of LINE1-containing transcripts restores TIL effector function. Our study identifies a role for LINE1 elements in maintaining T cell quiescence and suggests that an abundance of LINE1-containing transcripts is critical for T cell effector function and exhaustion.Non-canonical transcripts containing LINE1 transposable elements maintain naive CD4(+) T cell quiescence and interfere with gene expression in cis. LINE1-containing transcripts are downregulated upon T cell activation.
2022
CD4-Positive T-Lymphocytes
Chromatin
Heterogeneous-Nuclear Ribonucleoproteins
Histones
Humans
Interferon Regulatory Factors
Lymphocyte Activation
Lymphocytes, Tumor-Infiltrating
Mechanistic Target of Rapamycin Complex 1
Phosphoproteins
Polypyrimidine Tract-Binding Protein
RNA
RNA-Binding Proteins
Signal Transduction
Transcription Factors, TFII
Transcription, Genetic
Gene Expression Regulation
Long Interspersed Nucleotide Elements
RNA Splicing
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/64481
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