1. Long Noncoding RNA in Hematopoiesis and Immunity
Ansuman T. Satpathy, Howard Y. Chang 
Immunity 
Volume 42, Issue 5, Pages (May 2015)
DOI: /j.immuni
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2. Figure 1 Lineage-Specific Functions of lncRNAs
(A) Selectively expressed lncRNAs can regulate cell-fate decisions in the hematopoietic system; for example, lncRNAs can affect the differentiation of macrophage (blue) and dendritic cell (DC; green) lineages from a common myeloid progenitor (Carpenter et al., 2013; Wang et al., 2014). lncRNAs can also regulate the activation state of cell types, for example, by inducing distinct cytokine expression profiles in activated macrophages (pink) and DCs (orange) after pathogen recognition (Carpenter et al., 2013; Guttman et al., 2009).
(B) Lineage-specific lncRNA expression (1–3) can be induced by combinatorial transcription factor inputs (TF1–TF3) downstream of different signaling pathways (colored arrows). Transcription factors bind to DNA enhancer elements and activate expression of specific lncRNAs through interactions with Mediator and RNA polymerase II transcriptional complexes (light-pink circles on the left). lncRNAs modulate immune differentiation and activation through a variety of biochemical mechanisms, including chromatin modification, protein scaffolding, and direct mRNA interaction (right) (Wang and Chang, 2011). lncRNAs can recruit chromatin-modifying proteins to target gene loci by directly binding DNA elements or by bridging interactions between chromatin regulators and DNA-binding proteins (top right). Additional lncRNA-protein modules include decoy functions in signaling pathways, scaffolding of regulatory protein complexes, and allosteric modulation of protein function (middle right). Finally, base pairing of lncRNAs with target mRNAs can lead to decreased mRNA stability and/or translational efficiency (bottom right).
Immunity  , DOI: ( /j.immuni )
Copyright © 2015 Elsevier Inc. Terms and Conditions

3. Figure 2 lncRNAs Regulate Hematopoiesis and Immune Activation
LncRNAs that regulate immune system development and activation are shown next to the cellular stage at which they act (left panel). For several lncRNAs, their proposed mechanism of action and key target genes are shown (right panels). H19 and lnc-DC are examples of lncRNAs that control hematopoietic differentiation. H19 maintains long-term HSC quiescence and self-renewal (Venkatraman et al., 2013). H19 binds MBD1 (methyl-CpG-binding domain protein 1) and recruits methyltransferase complexes to place repressive methylation marks (red circles) on target imprinted loci (Monnier et al., 2013). lnc-DC controls DC differentiation by promoting phosphorylation and nuclear translocation of a key DC transcription factor, STAT3 (signal transducer and activator of transcription 3) (Wang et al., 2014). lnc-DC binds to STAT3 and inhibits its interaction with the tyrosine phosphatase SHP1 (Src homology region 2 domain-containing phosphatase 1). NRON (non-protein-coding RNA, repressor of NFAT) and NeST (Nettoie Salmonella pas Theiler's) are examples of lncRNAs that regulate adaptive immune responses. NRON restricts inappropriate activation of CD4+ T cells by sequestering phosphorylated NFAT (nuclear factor of activated T cells) in the cytoplasm in a large protein complex with IQGAP (IQ-motif-containing GTPase-activating protein 1) and LRRK2 (leucine-rich repeat kinase 2) (Willingham et al., 2005). Upon T cell activation, NFAT is dephosphorylated and enters the nucleus, where it can activate gene transcription. NeST is required for Ifng expression in CD8+ T cells and CD4+ T helper 1 (Th1) cells (Collier et al., 2012; Gomez et al., 2013). NeST binds WDR5 (WD-repeat-containing protein 5), the core subunit of the MLL (mixed lineage leukemia) methyltransferase complex, and recruits it to the Ifng locus, where it catalyzes H3K4 methylation (blue diamonds) and activates transcription. Finally, Lethe and lincRNA-Cox2 act in the innate immune response to regulate inflammatory gene transcription. Lethe is induced by IL-1β and TNF-α and acts as a NF-kB decoy molecule to limit inflammation (Rapicavoli et al., 2013). Lethe binds nuclear RelA homodimers and prevents their accumulation at target gene loci, including Il6. lincRNA-Cox2 is induced downstream of TLR activation in macrophages and DCs to repress and activate large gene sets (Carpenter et al., 2013). lincRNA-Cox2-dependent gene repression is mediated by its association with the heterogeneous nuclear RNA-binding proteins hnRNP-A/B and hnRNP-A2/B1.
Immunity  , DOI: ( /j.immuni )
Copyright © 2015 Elsevier Inc. Terms and Conditions