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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. We found that interstitial macrophage-derived IL-1β primes a subset of AT2 cells expressing Il1r1 for conversion into DATPs via a HIF1α-mediated glycolysis pathway, which is required for mature AT1 cell differentiation. Importantly, chronic inflammation mediated by IL-1β prevents AT1 differentiation, leading to aberrant accumulation of DATPs and impaired alveolar regeneration. Together, this stepwise mapping to cell fate transitions shows how an inflammatory niche controls alveolar regeneration by controlling stem cell fate and behavior.We would like to thank Emma Rawlins (University of Cambridge, UK) for valuable scientific discussions and sharing the mouse lines; We would like to thank Randall Johnson (University of Cambridge, UK) for sharing Hif1aflox/flox mouse line; Nisha Narayan and Brian Huntly for sharing materials and discussion on glycolysis experiments; Irina Pshenichnaya (Histology), Maike Paramor (NGS library), Peter Humphreys (Imaging), Andy Riddell (Flow cytometry), Simon McCallum (Flow cytometry, Cambridge NIHR BRC Cell Phenotyping Hub), Katarzyna Kania (single cell sequencing at Cancer Research UK), and Cambridge Stem Cell Institute core facilities for technical assistance; Papworth Hospital Research Tissue Bank for providing tissue samples from IPF and lung adenocarcinoma (T02233); Kelly Evans for sharing histology samples of human lung tissue samples; Seungmin Han and Woochang Hwang for discussion on the scRNA-seq analysis; Life Science Editors for editorial assistance; All Lee Lab members for helpful discussion. This work was supported by Wellcome and the Royal Society (107633/Z/15/Z) and European Research Council Starting Grant (679411). J.C. was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1A6A3A03005399)
Tunicate mitogenomics and phylogenetics: peculiarities of the Herdmania momus mitochondrial genome and support for the new chordate phylogeny
International audienceBACKGROUND: Tunicates represent a key metazoan group as the sister-group of vertebrates within chordates. The six complete mitochondrial genomes available so far for tunicates have revealed distinctive features. Extensive gene rearrangements and particularly high evolutionary rates have been evidenced with regard to other chordates. This peculiar evolutionary dynamics has hampered the reconstruction of tunicate phylogenetic relationships within chordates based on mitogenomic data. RESULTS: In order to further understand the atypical evolutionary dynamics of the mitochondrial genome of tunicates, we determined the complete sequence of the solitary ascidian Herdmania momus. This genome from a stolidobranch ascidian presents the typical tunicate gene content with 13 protein-coding genes, 2 rRNAs and 24 tRNAs which are all encoded on the same strand. However, it also presents a novel gene arrangement, highlighting the extreme plasticity of gene order observed in tunicate mitochondrial genomes. Probabilistic phylogenetic inferences were conducted on the concatenation of the 13 mitochondrial protein-coding genes from representatives of major metazoan phyla. We show that whereas standard homogeneous amino acid models support an artefactual sister position of tunicates relative to all other bilaterians, the CAT and CAT+BP site- and time-heterogeneous mixture models place tunicates as the sister-group of vertebrates within monophyletic chordates. Moreover, the reference phylogeny indicates that tunicate mitochondrial genomes have experienced a drastic acceleration in their evolutionary rate that equally affects protein-coding and ribosomal-RNA genes. CONCLUSION: This is the first mitogenomic study supporting the new chordate phylogeny revealed by recent phylogenomic analyses. It illustrates the beneficial effects of an increased taxon sampling coupled with the use of more realistic amino acid substitution models for the reconstruction of animal phylogeny
An updated 18S rRNA phylogeny of tunicates based on mixture and secondary structure models
<p>Abstract</p> <p>Background</p> <p>Tunicates have been recently revealed to be the closest living relatives of vertebrates. Yet, with more than 2500 described species, details of their evolutionary history are still obscure. From a molecular point of view, tunicate phylogenetic relationships have been mostly studied based on analyses of 18S rRNA sequences, which indicate several major clades at odds with the traditional class-level arrangements. Nonetheless, substantial uncertainty remains about the phylogenetic relationships and taxonomic status of key groups such as the Aplousobranchia, Appendicularia, and Thaliacea.</p> <p>Results</p> <p>Thirty new complete 18S rRNA sequences were acquired from previously unsampled tunicate species, with special focus on groups presenting high evolutionary rate. The updated 18S rRNA dataset has been aligned with respect to the constraint on homology imposed by the rRNA secondary structure. A probabilistic framework of phylogenetic reconstruction was adopted to accommodate the particular evolutionary dynamics of this ribosomal marker. Detailed Bayesian analyses were conducted under the non-parametric CAT mixture model accounting for site-specific heterogeneity of the evolutionary process, and under RNA-specific doublet models accommodating the occurrence of compensatory substitutions in stem regions. Our results support the division of tunicates into three major clades: 1) Phlebobranchia + Thaliacea + Aplousobranchia, 2) Appendicularia, and 3) Stolidobranchia, but the position of Appendicularia could not be firmly resolved. Our study additionally reveals that most Aplousobranchia evolve at extremely high rates involving changes in secondary structure of their 18S rRNA, with the exception of the family Clavelinidae, which appears to be slowly evolving. This extreme rate heterogeneity precluded resolving with certainty the exact phylogenetic placement of Aplousobranchia. Finally, the best fitting secondary-structure and CAT-mixture models suggest a sister-group relationship between Salpida and Pyrosomatida within Thaliacea.</p> <p>Conclusion</p> <p>An updated phylogenetic framework for tunicates is provided based on phylogenetic analyses using the most realistic evolutionary models currently available for ribosomal molecules and an unprecedented taxonomic sampling. Detailed analyses of the 18S rRNA gene allowed a clear definition of the major tunicate groups and revealed contrasting evolutionary dynamics among major lineages. The resolving power of this gene nevertheless appears limited within the clades composed of Phlebobranchia + Thaliacea + Aplousobranchia and Pyuridae + Styelidae, which were delineated as spots of low resolution. These limitations underline the need to develop new nuclear markers in order to further resolve the phylogeny of this keystone group in chordate evolution.</p
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. Much of their ecological success can be attributed to a diet of plant
storage organs, which has allowed them to colonize climatically varied habitats across sub-Saharan Africa, and has
probably contributed to the evolution of their diverse social systems. Yet despite their many remarkable phenotypic
specializations, little is known about molecular adaptations underlying these traits. To address this, we sequenced the
transcriptomes of seven mole-rat taxa, including three solitary species, and combined new sequences with existing
genomic data sets. Alignments of more than 13,000 protein-coding genes encompassed, for the first time, all six
genera and the full spectrum of ecological and social variation in the clade. We detected positive selection within the
mole-rat clade and along ancestral branches in approximately 700 genes including loci associated with tumorigenesis,
aging, morphological development, and sociality. By combining these results with gene ontology annotation and
protein–protein networks, we identified several clusters of functionally related genes. This family wide analysis of molecular
evolution in mole-rats has identified a suite of positively selected genes, deepening our understanding of the
extreme phenotypic traits exhibited by this group.The European Research Council (ERC Starting grant 310482 [EVOGENO]) awarded to S.J.R.; the DST-NRF SARChI Chair of Mammalian Behavioral
Ecology and Physiology (grant number 64756) (funds to N.C.B.).http://mbe.oxfordjournals.orghb201
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). However, whereas elevated longevity is likely to be common across all 19 bat families, the reported
amino acid substitutionswere only observed in two closely related bat families. To test the hypothesis that an altered
GH/IGF1 axis relates to the longevity of African mole-rats and bats,we compared and analysed the homologous
coding gene sequences in genomic and transcriptomic data from 26 bat species, five mole-rats and 38
outgroup species. Phylogenetic analyses of both genes recovered themajority of nodes in the currently accepted
species tree with high support. Compared to other clades, such as primates and carnivores, the bats and rodents
had longer branch lengths. The single 24 amino acid transmembrane domain of IGF1Rwas found to bemore conserved
across mammals compared to that of GHR.Within bats, considerable variation in the transmembrane domain
of GHR was found, including a previously unreported deletion in Emballonuridae. The transmembrane
domains of rodents were found to be more conserved, with mole-rats lacking uniquely conserved amino acid
substitutions. Molecular evolutionary analyses showed that both genes were under purifying selection in bats
andmole-rats. Our findings suggest thatwhile the previously documentedmutations may confer some additional
lifespan to Myotis bats, other, as yet unknown, genetic differences are likely to account for the long lifespans
observed in many bat and mole-rat species.DST–NRF SARChI Chair for Behavioural Ecology and Physiology (64756), the European Research Council (310482 EVOGENO) and the National Science Foundation (DEB-0949759).http//www.elsevier.com/locate/genehb201
Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.
N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex3,4. The m6A 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 unknown5-7. 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. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy
Genome-wide signatures of convergent evolution in echolocating mammals
Evolution is typically thought to proceed through divergence of genes, proteins, and ultimately phenotypes(1-3). However, similar traits might also evolve convergently in unrelated taxa due to similar selection pressures(4,5). Adaptive phenotypic convergence is widespread in nature, and recent results from a handful of genes have suggested that this phenomenon is powerful enough to also drive recurrent evolution at the sequence level(6-9). Where homoplasious substitutions do occur these have long been considered the result of neutral processes. However, recent studies have demonstrated that adaptive convergent sequence evolution can be detected in vertebrates using statistical methods that model parallel evolution(9,10) although the extent to which sequence convergence between genera occurs across genomes is unknown. Here we analyse genomic sequence data in mammals that have independently evolved echolocation and show for the first time that convergence is not a rare process restricted to a handful of loci but is instead widespread, continuously distributed and commonly driven by natural selection acting on a small number of sites per locus. Systematic analyses of convergent sequence evolution in 805,053 amino acids within 2,326 orthologous coding gene sequences compared across 22 mammals (including four new bat genomes) revealed signatures consistent with convergence in nearly 200 loci. Strong and significant support for convergence among bats and the dolphin was seen in numerous genes linked to hearing or deafness, consistent with an involvement in echolocation. Surprisingly we also found convergence in many genes linked to vision: the convergent signal of many sensory genes was robustly correlated with the strength of natural selection. This first attempt to detect genome-wide convergent sequence evolution across divergent taxa reveals the phenomenon to be much more pervasive than previously recognised
Data from: Additional molecular support for the new chordate phylogeny
Recent phylogenomic analyses have suggested tunicates instead of cephalochordates as the closest living relatives of vertebrates. In direct contradiction with the long accepted view of Euchordates, this new phylogenetic hypothesis for chordate evolution has been the object of some skepticism. We assembled an expanded phylogenomic dataset focused on deuterostomes. Maximum-likelihood using standard models and Bayesian phylogenetic analyses using the CAT site-heterogeneous mixture model of amino-acid replacement both provided unequivocal support for the sister-group relationship between tunicates and vertebrates (Olfactores). Chordates were recovered as monophyletic with cephalochordates as the most basal lineage. These results were robust to both gene sampling and missing data. New analyses of ribosomal rRNA also recovered Olfactores when compositional bias was alleviated. Despite the inclusion of 25 taxa representing all major lineages, the monophyly of deuterostomes remained poorly supported. The implications of these phylogenetic results for interpreting chordate evolution are discussed in light of recent advances from evolutionary developmental biology and genomics
Additional molecular support for the new chordate phylogeny.
International audienceRecent phylogenomic analyses have suggested tunicates instead of cephalochordates as the closest living relatives of vertebrates. In direct contradiction with the long accepted view of Euchordates, this new phylogenetic hypothesis for chordate evolution has been the object of some skepticism. We assembled an expanded phylogenomic dataset focused on deuterostomes. Maximum-likelihood using standard models and Bayesian phylogenetic analyses using the CAT site-heterogeneous mixture model of amino-acid replacement both provided unequivocal support for the sister-group relationship between tunicates and vertebrates (Olfactores). Chordates were recovered as monophyletic with cephalochordates as the most basal lineage. These results were robust to both gene sampling and missing data. New analyses of ribosomal rRNA also recovered Olfactores when compositional bias was alleviated. Despitethe inclusion of 25 taxa representing all major lineages, the monophyly of deuterostomes remained poorly supported. The implications of these phylogenetic results for interpreting chordate evolution are discussed in light of recent advances from evolutionary developmental biology and genomics. genesis 46:592-604, 2008. (c) 2008 Wiley-Liss, Inc
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