Author: Marasca, Federica, Sinha, Shruti, Vadal, 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, Sold, Giulia, Biffo, Stefano, Abrignani, Sergio, Bodega, Beatrice
Issue&Volume: 2022-01-17
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.
DOI: 10.1038/s41588-021-00989-7
Source: https://www.nature.com/articles/s41588-021-00989-7
Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex
本期文章:《自然—遗传学》:Online/在线发表