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.

LINE1 are spliced in non-canonical transcript variants to regulate T cell quiescence and exhaustion / F. Marasca, S. Sinha, R. Vadala, B. Polimeni, V. Ranzani, E.M. Paraboschi, F.V. Burattin, M. Ghilotti, M. Crosti, M.L. Negri, S. Campagnoli, S. Notarbartolo, A. Sartore-Bianchi, S. Siena, D. Prati, G. Montini, G. Viale, O. Torre, S. Harari, R. Grifantini, G. Solda, S. Biffo, S. Abrignani, B. Bodega. - In: NATURE GENETICS. - ISSN 1061-4036. - 54:2(2022 Feb), pp. 180-193. [10.1038/s41588-021-00989-7]

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

F. Marasca
Co-primo
;
S. Sinha
Co-primo
;
V. Ranzani;E.M. Paraboschi;F.V. Burattin;S. Notarbartolo;A. Sartore-Bianchi;S. Siena;G. Montini;G. Viale;S. Harari;S. Biffo;S. Abrignani
Penultimo
;
B. Bodega
Ultimo
2022-02

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.
Settore BIO/11 - Biologia Molecolare
17-gen-2022
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/903690
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