During an immune response to microbial infection, CD8+ T cells give rise to short-lived effector cells and memory cells that provide sustained protection. Although the transcriptional programs regulating CD8+ T cell differentiation have been extensively characterized, the role of long noncoding RNAs (lncRNAs) in this process remains poorly understood. Using a functional genetic knockdown screen, we identified the lncRNA Malat1 as a regulator of terminal effector cells and the terminal effector memory (t-TEM) circulating memory subset. Evaluation of chromatin-enriched lncRNAs revealed that Malat1 grouped with trans lncRNAs that exhibit increased RNA interactions at gene promoters and gene bodies. Moreover, we observed that Malat1 was associated with increased H3K27me3 deposition at a number of memory cell-associated genes through a direct interaction with Ezh2, thereby promoting terminal effector and t-TEM cell differentiation. Our findings suggest an important functional role of Malat1 in regulating CD8+ T cell differentiation and broaden the knowledge base of lncRNAs in CD8+ T cell biology.
The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression
Disclosures: G.W. Yeo is a co-founder, member of the Board of Directors, on the SAB, equity holder, and paid consultant for Locanabio and Eclipse BioInnovations. In addition, G.W. Yeo is a visiting professor at the National University of Singapore. G.W. Yeo’s interest(s) have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. J.T. Chang reported grants from Takeda and Eli Lilly outside the submitted work. No other disclosures were reported.
- Award Id(s): P30KC063491,P30CA023100,S10OD026929,NS047101,AI129973,BX005106,AI132122,AI123202,HG004659,GM124494,HG004659,DK098808
- Award Id(s): P30DK120515
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Jad N. Kanbar, Shengyun Ma, Eleanor S. Kim, Nadia S. Kurd, Matthew S. Tsai, Tiffani Tysl, Christella E. Widjaja, Abigail E. Limary, Brian Yee, Zhaoren He, Yajing Hao, Xiang-Dong Fu, Gene W. Yeo, Wendy J. Huang, John T. Chang; The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression. J Exp Med 6 June 2022; 219 (6): e20211756. doi: https://doi.org/10.1084/jem.20211756
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