意大利米兰大学Beatrice Bodega、Sergio Abrignani等研究人员合作发现，LINE1以非经典转录本变体的形式剪接来调节T细胞的静止和衰竭。该项研究成果于2022年1月17日在线发表在《自然—遗传学》杂志上。

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