LINE1 are spliced in non-canonical transcript variants to regulate T cell quiescence and exhaustion.
Nat Genet
; 54(2): 180-193, 2022 02.
Article
in En
| MEDLINE
| ID: mdl-35039641
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Chromatin
/
CD4-Positive T-Lymphocytes
/
RNA Splicing
/
Gene Expression Regulation
/
Long Interspersed Nucleotide Elements
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
2022
Document type:
Article
Affiliation country:
Italia