Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity.

Unlabelled: Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyl-transferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response.

Downregulation of Dystrophin Expression Occurs across Diverse Tumors, Correlates with the Age of Onset, Staging and Reduced Survival of Patients.

Altered dystrophin expression was found in some tumors and recent studies identified a developmental onset of Duchenne muscular dystrophy (DMD). Given that embryogenesis and carcinogenesis share many mechanisms, we analyzed a broad spectrum of tumors to establish whether dystrophin alteration evokes related outcomes. Transcriptomic, proteomic, and mutation datasets from fifty tumor tissues and matching controls (10,894 samples) and 140 corresponding tumor cell lines were analyzed.

Predicting genes associated with RNA methylation pathways using machine learning.

RNA methylation plays an important role in functional regulation of RNAs, and has thus attracted an increasing interest in biology and drug discovery. Here, we collected and collated transcriptomic, proteomic, structural and physical interaction data from the Harmonizome database, and applied supervised machine learning to predict novel genes associated with RNA methylation pathways in human. We selected five types of classifiers, which we trained and evaluated using cross-validation on multiple training sets.

Nectar-feeding bats and birds show parallel molecular adaptations in sugar metabolism enzymes.

In most vertebrates, the demand for glucose as the primary substrate for cellular respiration is met by the breakdown of complex carbohydrates, or energy is obtained by protein and lipid catabolism. In contrast, a few bat and bird species have convergently evolved to subsist on nectar, a sugar-rich mixture of glucose, fructose, and sucrose. How these nectar-feeders have adapted to cope with life-long high sugar intake while avoiding the onset of metabolic syndrome and diabetes is not understood.

Dietary Diversification and Specialization in Neotropical Bats Facilitated by Early Molecular Evolution.

Dietary adaptation is a major feature of phenotypic and ecological diversification, yet the genetic basis of dietary shifts is poorly understood. Among mammals, Neotropical leaf-nosed bats (family Phyllostomidae) show unmatched diversity in diet; from a putative insectivorous ancestor, phyllostomids have radiated to specialize on diverse food sources including blood, nectar, and fruit. To assess whether dietary diversification in this group was accompanied by molecular adaptations for changing metabolic demands, we sequenced 89 transcriptomes across 58 species and combined these with published data to compare ∼13,000 protein coding genes across 66 species.

Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.

N-methyladenosine (mA) is an abundant internal RNA modification that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex. The mA methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14.

Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration.

Tissue regeneration is a multi-step process mediated by diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here we leveraged single-cell RNA sequencing in combination with in vivo lineage tracing and organoid models to finely map the trajectories of alveolar-lineage cells during injury repair and lung regeneration. We identified a distinct AT2-lineage population, damage-associated transient progenitors (DATPs), that arises during alveolar regeneration.

Positive Selection and Inactivation in the Vision and Hearing Genes of Cetaceans.

The transition to an aquatic lifestyle in cetaceans (whales and dolphins) resulted in a radical transformation in their sensory systems. Toothed whales acquired specialized high-frequency hearing tied to the evolution of echolocation, whereas baleen whales evolved low-frequency hearing. More generally, all cetaceans show adaptations for hearing and seeing underwater.

Phylogenomic Resolution of the Cetacean Tree of Life Using Target Sequence Capture.

The evolution of cetaceans, from their early transition to an aquatic lifestyle to their subsequent diversification, has been the subject of numerous studies. However, although the higher-level relationships among cetacean families have been largely settled, several aspects of the systematics within these groups remain unresolved. Problematic clades include the oceanic dolphins (37 spp.

Resolving evolutionary relationships among six closely related taxa of the horseshoe bats (Rhinolophus) with targeted resequencing data.

Recently diverged taxa are often characterised by high rates of introgressive hybridization and incomplete lineage sorting, both of which can complicate phylogenetic reconstructions of species histories. Here we use a sequence capture approach to obtain genome-wide data to resolve the evolutionary relationships, and infer the extent and timescale of hybridization and introgression events, among six recently diverged taxa of the horseshoe bat species complexes Rhinolophus sinicus and R. thomasi.

A phylogenomic framework and timescale for comparative studies of tunicates.

Background: Tunicates are the closest relatives of vertebrates and are widely used as models to study the evolutionary developmental biology of chordates. Their phylogeny, however, remains poorly understood, and to date, only the 18S rRNA nuclear gene and mitogenomes have been used to delineate the major groups of tunicates. To resolve their evolutionary relationships and provide a first estimate of their divergence times, we used a transcriptomic approach to build a phylogenomic dataset including all major tunicate lineages, consisting of 258 evolutionarily conserved orthologous genes from representative species.

Comparative genomics reveals contraction in olfactory receptor genes in bats.

Gene loss and gain during genome evolution are thought to play important roles in adaptive phenotypic diversification. Among mammals, bats possess the smallest genomes and have evolved the unique abilities of powered flight and laryngeal echolocation. To investigate whether gene family evolution has contributed to the genome downsizing and phenotypic diversification in this group, we performed comparative evolutionary analyses of complete proteome data for eight bat species, including echolocating and non-echolocating forms, together with the proteomes of 12 other laurasiatherian mammals.

Family Wide Molecular Adaptations to Underground Life in African Mole-Rats Revealed by Phylogenomic Analysis.

During their evolutionary radiation, mammals have colonized diverse habitats. Arguably the subterranean niche is the most inhospitable of these, characterized by reduced oxygen, elevated carbon dioxide, absence of light, scarcity of food, and a substrate that is energetically costly to burrow through. Of all lineages to have transitioned to a subterranean niche, African mole-rats are one of the most successful.

Divergent evolutionary rates in vertebrate and mammalian specific conserved non-coding elements (CNEs) in echolocating mammals.

Background: The majority of DNA contained within vertebrate genomes is non-coding, with a certain proportion of this thought to play regulatory roles during development. Conserved Non-coding Elements (CNEs) are an abundant group of putative regulatory sequences that are highly conserved across divergent groups and thus assumed to be under strong selective constraint. Many CNEs may contain regulatory factor binding sites, and their frequent spatial association with key developmental genes - such as those regulating sensory system development - suggests crucial roles in regulating gene expression and cellular patterning.

Comparative population genomics in animals uncovers the determinants of genetic diversity.

Genetic diversity is the amount of variation observed between DNA sequences from distinct individuals of a given species. This pivotal concept of population genetics has implications for species health, domestication, management and conservation. Levels of genetic diversity seem to vary greatly in natural populations and species, but the determinants of this variation, and particularly the relative influences of species biology and ecology versus population history, are still largely mysterious.

Molecular evolution of growth hormone and insulin-like growth factor 1 receptors in long-lived, small-bodied mammals.

Mammals typically display a robust positive relationship between lifespan and body size. Two groups that deviate markedly from this pattern are bats and African mole-rats, with members of both groups being extremely long-lived given their body size, with the maximum documented lifespan for many species exceeding 20 years. A recent genomics study of the exceptionally long-lived Brandt's bat, Myotis brandtii (41 years), suggested that its longevity and small body size may be at least partly attributed to key amino acid substitutions in the transmembrane domains of the receptors of growth hormone (GH) and insulin-like growth factor 1 (IGF1).

Phylogenomic analyses elucidate the evolutionary relationships of bats.

Molecular phylogenetics has rapidly established the evolutionary positions of most major mammal groups, yet analyses have repeatedly failed to agree on that of bats (order Chiroptera). Moreover, the relationship among the major bat lineages has proven equally contentious, with ongoing disagreements about whether echolocating bats are paraphyletic or a true group having profound implications for whether echolocation evolved once or possibly multiple times. By generating new bat genome data and applying model-based phylogenomic analyses designed to accommodate heterogeneous evolutionary processes, we show that-contrary to recent suggestions-bats are not closely related to odd-toed ungulates but instead have a more ancient origin as sister group to a large clade of carnivores, ungulates, and cetaceans.

Crossing the species barrier: genomic hotspots of introgression between two highly divergent Ciona intestinalis species.

Inferring a realistic demographic model from genetic data is an important challenge to gain insights into the historical events during the speciation process and to detect molecular signatures of selection along genomes. Recent advances in divergence population genetics have reported that speciation in face of gene flow occurred more frequently than theoretically expected, but the approaches used did not account for genome-wide heterogeneity (GWH) in introgression rates. Here, we investigate the impact of GWH on the inference of divergence with gene flow between two cryptic species of the marine model Ciona intestinalis by analyzing polymorphism and divergence patterns in 852 protein-coding sequence loci.

The population genomics of a fast evolver: high levels of diversity, functional constraint, and molecular adaptation in the tunicate Ciona intestinalis.

Phylogenomics has revealed the existence of fast-evolving animal phyla in which the amino acid substitution rate, averaged across many proteins, is consistently higher than in other lineages. The reasons for such differences in proteome-wide evolutionary rates are still unknown, largely because only a handful of species offer within-species genomic data from which molecular evolutionary processes can be deduced. In this study, we use next-generation sequencing technologies and individual whole-transcriptome sequencing to gather extensive polymorphism sequence data sets from Ciona intestinalis.

Reference-free transcriptome assembly in non-model animals from next-generation sequencing data.

Next-generation sequencing (NGS) technologies offer the opportunity for population genomic study of non-model organisms sampled in the wild. The transcriptome is a convenient and popular target for such purposes. However, designing genetic markers from NGS transcriptome data requires assembling gene-coding sequences out of short reads.

Next-generation sequencing of transcriptomes: a guide to RNA isolation in nonmodel animals.

Next Generation Sequencing technologies (NGS) are rapidly invading many evolutionary and ecological fields, such as phylogenomics, molecular evolution, population genomics and molecular ecology. Among the potential targets of NGS is transcriptome sequencing, a fast and relatively cheap way to generate massive amounts of coding sequence data, offering promising perspectives for the analysis of molecular diversity in the wild. A number of molecular ecology research groups therefore may switch from DNA-based to RNA-based typing in the near future.