Fondazione INGM “Romeo ed Enrica Invernizzi”, Università degli Studi di Milan, ITALY
Decoding how Retrotransposable Elements regulate T cell functions in health and disease
Host: G. Del Sal
Abstract
Retrotransposons are emerging as a major source of regulatory RNAs across health and disease. To investigate their functional impact, within the Fantom_6 consortium we generated the first comprehensive atlas of end-to-end retrotransposon(RE)-transcripts across diverse human cell types—including T cells, neurons, and macrophages—using CapTrap ONT-seq. We discovered that 39% of human transcripts contain RE, the majority of which are non- coding and multi-exonic. DNA mapping via RADICL-seq revealed that specific RE families are selectively associated with chromatin, contributing to transcriptional plasticity and to establish cell identity. We focused on LINE1-transcripts in human T cells and found they act as regulators of gene expression at chromatin in quiescent and dysfunctional st ates, as tumor-infiltrating and aged T cells. During T cell activation, they are actively silenced via splicing.
Importantly, antisense oligonucleotide (ASO)-mediated depletion of LINE1-transcripts reactivates dysfunctional T cells, positioning them as nuclear immune checkpoints and compelling therapeutic targets. Mechanistically, LINE1 RNAs interact with NUCLEOLIN and Trim28 to organize open chromatin compartments through phase separation and regulate protein synthesis—critical for T cell function. Altogether, our findings uncover a previously hidden layer of gene regulation and highlight RE-RNAs as powerful modulators of cellular identity, with broad implications for immunotherapy and regenerative medicine.
International Seminar Programme
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