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Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3–KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment. Lipopolysaccharide derived from gut bacteria can accelerate the formation of cerebral cavernous malformations by activating TLR4 on endothelial cells, and polymorphisms that increase expression of the genes encoding TLR4 or its co-receptor CD14 are associated with higher CCM lesion burden in humans. Microbiome driven cerebral malformations Cerebral cavernous malformations (CCMs) are malformations of the vascular system, seen mainly in the brain where they can cause haemorrhagic stroke and seizures. CCMs arise from loss-of-function mutations in components of a complex that negatively regulates MEKK3–KLF2/4 signalling and Rho/ROCK signalling in brain endothelial cells. Mark Kahn and colleagues now identify upstream regulators that activate this pathway in brain endothelial cells. They find that lipopolysaccharide derived from gut bacteria can accelerate CCM formation by activating TLR4 on endothelial cells. The authors further show that polymorphisms in the TLR4 gene or CD14 , the gene encoding its co-receptor, are associated with higher CCM lesion burden in humans. These findings suggest that the gut microbiome and TLR4 are important drivers of CCMs and represent potential therapeutic targets.

The long non-coding RNA Morrbid controls myeloid cell lifespan and regulates apoptosis by repressing the adjacent pro-apoptotic Bcl2l11 gene in cis . Keeping myeloid cells on a tight leash Neutrophils, eosinophils and 'classical' monocytes are a first line of defense against pathogens, but their actions can also cause inflammatory diseases. It is important that the lifespan of these myeloid cells is regulated in order to minimize deleterious effects. Jorge Henao-Mejia and colleagues show here that a long non-coding RNA termed Morrbid specifically controls the lifespan of short-lived myeloid cells by regulating expression of the pro-apoptotic Bcl2l11 ( Bim ) gene. MORRBID is present in humans and is highly upregulated in human hypereosinophilic diseases, so its inhibition may represent a novel therapeutic approach in pathologies influenced by altered myeloid lifespan. Neutrophils, eosinophils and ‘classical’ monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body 1 , 2 . Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation 1 , 2 . However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid , which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as Bim ), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis , enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.

In systemic lupus erythematosus (lupus), environmental effects acting within a permissive genetic background lead to autoimmune dysregulation. Dysfunction of CD4+ T cells contributes to pathology by providing help to autoreactive B and T cells, and CD4+ T cell dysfunction coincides with altered DNA methylation and histone modifications of select gene loci. However, chromatin accessibility states of distinct T cell subsets and mechanisms driving heterogeneous chromatin states across patients remain poorly understood. We defined the transcriptome and epigenome of multiple CD4+ T cell populations from patients with lupus and healthy individuals. Most patients with lupus, regardless of disease activity, had enhanced chromatin accessibility bearing hallmarks of inflammatory cytokine signals. Single-cell approaches revealed that chromatin changes extended to naive CD4+ T cells, uniformly affecting naive subpopulations. Transcriptional data and cellular and protein analyses suggested that the TNF family members, TNF-α, LIGHT, and TWEAK, were linked to observed molecular changes and the altered lupus chromatin state. However, we identified a patient subgroup prescribed angiotensin receptor blockers (ARBs), which lacked TNF-linked lupus chromatin accessibility features. These data raise questions about the role of lupus-associated chromatin changes in naive CD4+ T cell activation and differentiation and implicate ARBs in the regulation of disease-driven epigenetic states.

Diabetes mellitus (DM) is a risk factor for cancer. The role of DM-induced hyperglycemic (HG) stress in blood cancer is poorly understood. Epidemiologic studies show that individuals with DM are more likely to have a higher rate of mutations in genes found in pre-leukemic hematopoietic stem and progenitor cells (pre-LHSPCs) including TET2. TET2-mutant pre-LHSPCs require additional hits to evolve into full-blown leukemia and/or an aggressive myeloproliferative neoplasm (MPN). Intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the extrinsic factors are poorly understood. Using a mouse model carrying Tet2 haploinsufficiency to mimic the human pre-LHSPC condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces hyperglycemia and type 1 DM, we show that the compound mutant mice developed a lethal form of MPN and/or acute myeloid leukemia (AML). RNA-Seq revealed that this was due in part to upregulation of proinflammatory pathways, thereby generating a feed-forward loop, including expression of the antiapoptotic, long noncoding RNA (lncRNA) Morrbid. Loss of Morrbid in the compound mutants rescued the lethality and mitigated MPN/AML. We describe a mouse model for age-dependent MPN/AML and suggest that hyperglycemia acts as an environmental driver for myeloid neoplasms, which could be prevented by reducing expression levels of the inflammation-related lncRNA Morrbid.

Viruses are parasitic entities that lack the basic metabolic machinery required to provide the energy and biosynthetic building blocks needed for their replication. To overcome this obstacle, viruses hijack the cellular metabolic machinery of their hosts in order to complete their life cycle and propagate. Yet, how viruses rewire cellular metabolic pathways remains poorly understood. On page 1051 of this issue, Wang et al. (1) identify a long noncoding RNA (lncRNA) called lncRNA-ACOD1 that is potently induced by multiple viruses, including vesicular stomatitis virus, vaccinia virus, and herpes simplex virus 1, in several mouse tissues, as well as by influenza virus in several human cell lines. This lncRNA promotes viral replication through the activation of the metabolic enzyme glutamic-oxaloacetic transaminase 2 (GOT2). Importantly, as enhancement of GOT2 activity by lncRNA-ACOD1 is required for optimal viral replication, mouse and human cells are dramatically protected from infection by simply down-regulating the amounts of this single lncRNA. Thus, this work uncovers a critical evolutionarily conserved mechanism by which viruses co-opt cellular metabolism for their own benefit. Moreover, it unveils a previously uncharacterized function of lncRNAs that could potentially be exploited for the development of new antiviral therapeutics.

The transcriptional programs that regulate CD8 T-cell differentiation and function in the context of viral infections or tumor immune surveillance have been extensively studied; yet how long noncoding RNAs (lncRNAs) and the loci that transcribe them contribute to the regulation of CD8 T cells during viral infections remains largely unexplored. Here, we report that transcription of the lncRNA Morrbid is specifically induced by T-cell receptor (TCR) and type I IFN stimulation during the early stages of acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. In response to type I IFN, the Morrbid RNA and its locus control CD8 T cell expansion, survival, and effector function by regulating the expression of the proapoptotic factor, Bcl2l11, and by modulating the strength of the PI3K–AKT signaling pathway. Thus, our results demonstrate that inflammatory cue-responsive lncRNA loci represent fundamental mechanisms by which CD8 T cells are regulated in response to pathogens and potentially cancer.

Diabetes mellitus (DM) is a risk factor for cancer. The role of DM-induced hyperglycemic (HG) stress in blood cancer is poorly understood. Epidemiologic studies show that individuals with DM are more likely to have a higher rate of mutations in genes found in pre-leukemic hematopoietic stem and progenitor cells (pre-LHSPCs) including TET2. TET2-mutant pre-LHSPCs require additional hits to evolve into full-blown leukemia and/or an aggressive myeloproliferative neoplasm (MPN). Intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the extrinsic factors are poorly understood. Using a mouse model carrying Tet2 haploinsufficiency to mimic the human pre-LHSPC condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces hyperglycemia and type 1 DM, we show that the compound mutant mice developed a lethal form of MPN and/or acute myeloid leukemia (AML). RNA-Seq revealed that this was due in part to upregulation of proinflammatory pathways, thereby generating a feed-forward loop, including expression of the antiapoptotic, long noncoding RNA (lncRNA) Morrbid. Loss of Morrbid in the compound mutants rescued the lethality and mitigated MPN/AML. We describe a mouse model for age-dependent MPN/AML and suggest that hyperglycemia acts as an environmental driver for myeloid neoplasms, which could be prevented by reducing expression levels of the inflammation-related lncRNA Morrbid.

The immune system is comprised of diverse cell types that work together to protect the host from infection and maintain tissue homeostasis. To achieve this complex balance, extracellular cues determine highly specific epigenetic landscapes and transcriptional profiles of each immune cell subtype. New evidence indicates that long non-coding RNAs (lncRNAs) play critical roles in epigenetic and transcriptional regulation in mammals. Here we identify the lncRNA Morrbid, and examine its role in immune function. In Chapter 2, we assess the function of Morrbid at homeostasis and describe its role in finely tuning the lifespan of short-lived myeloid cells. In Chapter 3, we examine Morrbid under inflammatory conditions and illustrate its role in restraining CD8 T cell responses following viral infection. These data demonstrate that lncRNAs can function as highly cell-type specific effectors of extracellular cues to control immunological processes that require rapid and strict regulation.