Evolving Views of Long Noncoding RNAs and Epigenomic Control of Lymphocyte State and Memory

Abstract

Not simply an attribute of the adaptive immune system, immunological memory can be viewed on multiple levels. Accordingly, the molecular basis of memory comprises multiple mechanisms. The advent of new sequencing technologies has greatly enhanced the understanding of gene regulation and lymphocyte specification, and improved measurement of chromatin states affords new insights into the epigenomic and transcriptomic programs that underlie memory. Beyond canonical genes, the involvement of long noncoding RNAs (lncRNAs) is becoming increasingly apparent, and it appears that there are more than two to three times as many lncRNAs as protein-coding genes. lncRNAs can directly interact with DNA, RNA, and proteins, and a single lncRNA can contain multiple modular domains and thus interact with different classes of molecules. Yet, most lncRNAs have not been tested for function, and even fewer knockout mice have been generated. It is therefore timely to consider new potential mechanisms that may contribute to immune memory.

Figure 1.

Molecular mechanisms of long noncoding RNAs (lncRNAs) identified in immune cells. Illustration of lncRNAs identified in immune cells that have diverse cellular functions. (A) In macrophages, lncRNA Sros1 controls cytoplasmic protein expression through interaction with the RNA-binding protein, CAPRIN1, which destabilizes Stat1 messenger RNA (mRNA) and impedes its translation. (B) Rroid is specifically expressed in group 1 innate lymphoid cells (ILCs); however, the locus, not the transcript, is functionally relevant. In response to IL-15, Rroid acts as a cis-regulatory element to promote deposition of Stat5 at the Id2 promoter to enhance expression, which is required for ILC specification. Deletion of Rroid inhibits Id2 expression. (C) In Th1 cells, both the Ifng-as1 transcript and locus regulate gene expression in cis. T cells that lack expression of the lncRNA have reduced levels of Ifng, whereas cells with deletion of Ifng-as1 do not maintain chromatin architecture required for optimal expression of Ifng. (D) The lncRNA Morrbid has a dual cell-specific role. In neutrophils, eosinophils, and monocytes, prosurvival cytokines induce the expression of Morrbid to promote cell expansion and survival. Morrbid binds to the Bcl2l11 promoter, facilitating the PRC2 histone methyltransferase complex to associate with the promoter and inhibit expression of Bcl2l11. In CD8 T cells, induction of Morrbid by type 1 IFNs inhibits activation of the AKT signaling pathway, limiting cell expansion and effector function.