Study of Transcriptional and Post-transcriptional Regulation in Immune Systems
Open AccessT lymphocyte is a central player in mounting protective cellular immune responses against pathogenic antigens and malignantly transformed cells. Therefore, it is critically important to understand the gene regulatory network underscoring its identity and function. T cell identity is established during thymic development, but how it is maintained in periphery remains unknown. Here we found that ablating transcription factors (TFs) Tcf1 and Lef1 in mature CD8+ T cells aberrantly induces genes that are signatures of non-T cell immune lineages. Using high-throughput chromosome-conformation-capture sequencing, we demonstrate that Tcf1/Lef1 TFs are critical for maintaining three-dimensional (3D) genome organization at multiple scales in CD8+ T cells. We developed a novel algorithm, HiCHub, to characterize the coordinated changes of chromatin interactions at intermediate scales using network-based approaches. Comprehensive network analysis coupled with genome-wide profiling of chromatin accessibility and Tcf1 occupancy reveals the direct impact of Tcf1/Lef1 on T-cell genome is to promote formation of extensively interconnected hubs through enforcing chromatin interaction and accessibility. This integrative mechanism utilized by Tcf1/Lef1 achieves not only transcriptional activation of T-cell identity genes but also repression of non-T lineage genes, providing constant supervision of CD8+ T cell identity. In addition to transcription regulation, our previous work identified post-translational regulation in T cell activation. Motivated by our previous finding that intron retention (IR) could lead to transcript instability, we monitored the expression dynamics of nascent transcripts in resting and activated CD4+ T cells. Using computational modeling we found a global stabilization of spliced mRNAs upon T cell activation. In addition, we identified that La-related protein 4 (LARP4), an RNA-binding protein known to enhance mRNA stability, was involved in T cell activation-dependent mRNA stabilization. Knocking out Larp4 in mice destabilized Nfκb1 mRNAs and reduced secretion of interleukin-2 (IL2) and interferon-gamma (IFNγ), two factors critical for T cell proliferation and function. We propose that coordination between splicing regulation and mRNA stability may provide a novel paradigm to control spatiotemporal gene expression during T cell activation. Together, our work contributes to unraveling novel mechanisms of gene regulation in the immune system, deepening our understandings of immune response and immune cell identity, and potentially enhancing our ability to diagnosis and treat diseases in the future.
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