Polyamine metabolism is a central determinant of helper T cell lineage fidelity.

Polyamine synthesis represents one of the most profound metabolic changes during T cell activation, but the biological implications of this are scarcely known. Here, we show that polyamine metabolism is a fundamental process governing the ability of CD4+ helper T cells (TH) to polarize into different functional fates. Deficiency in ornithine decarboxylase, a crucial enzyme for polyamine synthesis, results in a severe failure of CD4+ T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage-defining transcription factors across TH cell subsets. Polyamines control TH differentiation by providing substrates for deoxyhypusine synthase, which synthesizes the amino acid hypusine, and mice in which T cells are deficient for hypusine develop severe intestinal inflammatory disease. Polyamine-hypusine deficiency caused widespread epigenetic remodeling driven by alterations in histone acetylation and a re-wired tricarboxylic acid (TCA) cycle. Thus, polyamine metabolism is critical for maintaining the epigenome to focus TH cell subset fidelity.

An LKB1-mitochondria axis controls TH17 effector function.

CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.

Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10.

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.

Autophagy orchestrates the crosstalk between cells and organs.

Over the recent years, it has become apparent that a deeper understanding of cell-to-cell and organ-to-organ communication is necessary to fully comprehend both homeostatic and pathological states. Autophagy is indispensable for cellular development, function, and homeostasis. A crucial aspect is that autophagy can also mediate these processes through its secretory role. The autophagy-derived secretome relays its extracellular signals in the form of nutrients, proteins, mitochondria, and extracellular vesicles. These crosstalk mediators functionally shape cell fate decisions, tissue microenvironment and systemic physiology. The diversity of the secreted cargo elicits an equally diverse type of responses, which span over metabolic, inflammatory, and structural adaptations in disease and homeostasis. We review here the emerging role of the autophagy-derived secretome in the communication between different cell types and organs and discuss the mechanisms involved.

MicroRNA epigenetic signatures in human disease.

MicroRNAs (miRNAs) are short non-coding RNAs that act as important regulators of gene expression as part of the epigenetic machinery. In addition to posttranscriptional gene silencing by miRNAs, the epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of complex diseases, such as late onset and fluctuation of symptoms. However, miRNAs not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenome and miRNome, and any dysregulation of this complex system can result in various physiological and pathological conditions. In addition, miRNAs play an important role in toxicogenomics and may explain the relationship between toxicant exposure and tumorigenesis. The present review provides information on 63 miRNA genes shown to be epigenetically regulated in association with 21 diseases, including 11 cancer types: cardiac fibrosis, cardiovascular disease, preeclampsia, Hirschsprung's disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, temporal lobe epilepsy, autism, pulmonary fibrosis, melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal, gastric, cervical, ovarian, prostate, lung, breast, and bladder cancer. The review revealed that hsa-miR-34a, hsa-miR-34b, and hsa-miR-34c are the most frequently reported epigenetically dysregulated miRNAs. There is a need to further study molecular mechanisms of various diseases to better understand the crosstalk between epigenetics and gene expression and to develop new therapeutic options and biomarkers.

MicroRNA-Target Interactions Reloaded: Identification of Potentially Functional Sequence Variants Within Validated MicroRNA-Target Interactions.

MicroRNAs (miRNAs) serve as critical regulators of gene expression. However, their binding to target genes can be influenced by genetic variability within the miRNA-target interaction (MTI) sites. We performed an in silico sequence reanalysis to identify novel sequence variants within MTIs with potential functional impacts. A literature search of the PubMed and the Web of Science spanning the years 2008 to April 2018 identified 240 articles reporting MTIs in humans. Sequence reanalysis of reported MTI regions was performed using the Ensembl browser. We found 76 sequence variants within 23 MTIs. We present description of MTIs wherein sequence variants are present within both the mature miRNA seed region and the miRNA target, which we termed miR-gene-target-single nucleotide polymorphism (miR-GenTar-SNP). To the best of our knowledge, this is the first report on copresence of sequence variants within both miRNA gene and the target site. In the course our analyses, the need for extension of current terminology emerged and therefore, novel terminology was introduced: miR-indel, miR-double nucleotide polymorphism (DNP), miR-TS-indel, and miR-TS-DNP. Identification of novel MTI sequence variants is a hitherto understudied, but critical dimension in understanding the complexity of interactions and gene deregulation in various complex diseases. Because such variations might profoundly affect miRNA function, they should be taken into consideration in future research that depends on "variability science" such as precision medicine, human genetics, and genomics in the study of complex diseases. The findings presented herein offer a baseline for further systematic reanalysis of all reported MTIs in human and other species.

Minimal Standards for Reporting microRNA:Target Interactions.

Epigenomics is one of the leading frontiers of postgenomics medicine. The challenges and prospects ahead in epigenomics are related not merely to technology innovation and clinical implementation but also to science communication. In this context, microRNAs (miRNAs) are an important part of the epigenomic regulatory machinery. As the number of publications reporting miRNA-target interactions (MTIs) is growing rapidly, there is an urgent need to standardize reporting. This study reports (1) an analysis of the published literature and databases reporting validated MTIs, and for the first time to the best of our knowledge (2) suggests a solution as a way forward, the minimum information required for MTI standard reporting. We retrieved the research reports from PubMed and Web of Science dating from 09/2006 to 01/2017 and downloaded information from DIANA-TarBase, miRecords, and miRTarBase. We evaluated the reporting and extracted MTI data, which we complemented with relevant genomic information. We suggest a standard minimum checklist for MTI reporting, consisting of seven pertinent data types: miRNA gene, target gene, species, experimental validation, sequence variants, associated phenotype, and additionally a PubMed identification (PMID) number in systematic reviews and meta-analyses. Our proposal reported here shall enable faster development of MTI databases and bioinformatics resources, and looking into the future, more efficient planning of experimental designs in the nascent field of epigenomics and its postgenomics applications.