Although autophagy is being pursued as a therapeutic target in clinical oncology trials, its effects on metastasis, the principal cause of cancer mortality, remain unclear. Here, we utilize mammary ...cancer models to temporally delete essential autophagy regulators during carcinoma progression. Though genetic ablation of autophagy strongly attenuates primary mammary tumor growth, impaired autophagy promotes spontaneous metastasis and enables the outgrowth of disseminated tumor cells into overt macro-metastases. Transcriptomic analysis reveals that autophagy deficiency elicits a subpopulation of otherwise luminal tumor cells exhibiting basal differentiation traits, which is reversed upon preventing accumulation of the autophagy cargo receptor, Neighbor to BRCA1 (NBR1). Furthermore, pharmacological and genetic induction of autophagy suppresses pro-metastatic differentiation and metastatic outgrowth. Analysis of human breast cancer data reveal that autophagy gene expression inversely correlates with pro-metastatic differentiation signatures and predicts overall and distant metastasis-free survival. Overall, these findings highlight autophagy-dependent control of NBR1 as a key determinant of metastatic progression.
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•Autophagy promotes primary tumor growth, yet suppresses metastatic outgrowth•Autophagy deficiency elicits a pro-metastatic basal tumor cell subpopulation•NBR1 accumulation mediates the effects of autophagy inhibition on metastasis•Enforced autophagy induction prevents the outgrowth of disseminated tumor cells
Autophagy is a therapeutic target in cancer, but its role during metastasis remains incompletely understood. In mammary cancer models, Marsh et al. demonstrate that autophagic degradation of NBR1 suppresses metastatic outgrowth by restricting an aggressive, basal subpopulation of tumor cells. Enforced autophagy is a potential therapeutic approach to prevent metastases.
Alternative splicing (AS) is a major source of transcript and proteome diversity, but examining AS in species without well‐annotated reference genomes remains difficult. Research on both human and ...mouse has demonstrated the advantages of using Iso‐Seq™ data for isoform‐level transcriptome analysis, including the study of AS and gene fusion. We applied Iso‐Seq™ to investigate AS in Amborella trichopoda, a phylogenetically pivotal species that is sister to all other living angiosperms. Our data show that, compared with RNA‐Seq data, the Iso‐Seq™ platform provides better recovery on large transcripts, new gene locus identification and gene model correction. Reference‐based AS detection with Iso‐Seq™ data identifies AS within a higher fraction of multi‐exonic genes than observed for published RNA‐Seq analysis (45.8% vs. 37.5%). These data demonstrate that the Iso‐Seq™ approach is useful for detecting AS events. Using the Iso‐Seq‐defined transcript collection in Amborella as a reference, we further describe a pipeline for detection of AS isoforms from PacBio Iso‐Seq™ without using a reference sequence (de novo). Results using this pipeline show a 66%–76% overall success rate in identifying AS events. This de novoAS detection pipeline provides a method to accurately characterize and identify bona fide alternatively spliced transcripts in any nonmodel system that lacks a reference genome sequence. Hence, our pipeline has huge potential applications and benefits to the broader biology community.
Premise of the Study
Conifers are an important living seed plant lineage with an extensive fossil record spanning more than 300 million years. The group therefore provides an excellent opportunity to ...explore congruence and conflict between dated molecular phylogenies and the fossil record.
Methods
We surveyed the current state of knowledge in conifer phylogenetics to present a new time‐calibrated molecular tree that samples ~90% of extant species diversity. We compared phylogenetic relationships and estimated divergence ages in this new phylogeny with the paleobotanical record, focusing on clades that are species‐rich and well known from fossils.
Key Results
Molecular topologies and estimated divergence ages largely agree with the fossil record in Cupressaceae, conflict with it in Araucariaceae, and are ambiguous in Pinaceae and Podocarpaceae. Molecular phylogenies provide insights into some fundamental questions in conifer evolution, such as the origin of their seed cones, but using them to reconstruct the evolutionary history of specific traits can be challenging.
Conclusions
Molecular phylogenies are useful for answering deep questions in conifer evolution if they depend on understanding relationships among extant lineages. Because of extinction, however, molecular datasets poorly sample diversity from periods much earlier than the Late Cretaceous. This fundamentally limits their utility for understanding deep patterns of character evolution and resolving the overall pattern of conifer phylogeny.
Adaptation in plant genomes Mei, Wenbin; Stetter, Markus G.; Gates, Daniel J. ...
American journal of botany,
01/2018, Volume:
105, Issue:
1
Journal Article
Peer reviewed
Open access
Since their origin 160 million years ago, flowering plants have rapidly diversified into more than 300,000 species, adapting to a striking array of habitats and conditions. Given their diversity and ...importance, a considerable body of research has been devoted to understanding plant adaptation (Tiffin and Ross-Ibarra, 2014), but the relative importance of the various factors that may impact the process of adaptation are still not well understood. Here Mel et al propose that genome size may play a previously under-appreciated role in determining how plants adapt. Rather than focus on the mechanisms of genome size variation or the adaptive significance of genome size itself, our functional space hypothesis predicts that interspecific differences in genome size may affect the process of adaptation by changing the number and location of potentially functional mutations.
Identifying and characterizing alternative splicing (AS) enables our understanding of the biological role of transcript isoform diversity. This study describes the use of publicly available RNA-Seq ...data to identify and characterize the global diversity of AS isoforms in maize using the inbred lines B73 and Mo17, and a related species, sorghum. Identification and characterization of AS within maize tissues revealed that genes expressed in seed exhibit the largest differential AS relative to other tissues examined. Additionally, differences in AS between the two genotypes B73 and Mo17 are greatest within genes expressed in seed. We demonstrate that changes in the level of alternatively spliced transcripts (intron retention and exon skipping) do not solely reflect differences in total transcript abundance, and we present evidence that intron retention may act to fine-tune gene expression across seed development stages. Furthermore, we have identified temperature sensitive AS in maize and demonstrate that drought-induced changes in AS involve distinct sets of genes in reproductive and vegetative tissues. Examining our identified AS isoforms within B73 × Mo17 recombinant inbred lines (RILs) identified splicing QTL (sQTL). The 43.3% of
sQTL regulated junctions are actually identified as alternatively spliced junctions in our analysis, while 10 Mb windows on each side of 48.2% of
-sQTLs overlap with splicing related genes. Using sorghum as an out-group enabled direct examination of loss or conservation of AS between homeologous genes representing the two subgenomes of maize. We identify several instances where AS isoforms that are conserved between one maize homeolog and its sorghum ortholog are absent from the second maize homeolog, suggesting that these AS isoforms may have been lost after the maize whole genome duplication event. This comprehensive analysis provides new insights into the complexity of AS in maize.
Evolution of the 3R-MYB Gene Family in Plants Feng, Guanqiao; Burleigh, John Gordon; Braun, Edward L ...
Genome biology and evolution,
2017-Apr-01, 2017-04-01, 20170401, Volume:
9, Issue:
4
Journal Article
Open access
Plant 3R-MYB transcription factors are an important subgroup of the MYB super family in plants; however, their evolutionary history and functions remain poorly understood. We identified 225 3R-MYB ...proteins from 65 plant species, including algae and all major lineages of land plants. Two segmental duplication events preceding the common ancestor of angiosperms have given rise to three subgroups of the 3R-MYB proteins. Five conserved introns in the domain region of the 3R-MYB genes were identified, which arose through a step-wise pattern of intron gain during plant evolution. Alternative splicing (AS) analysis of selected species revealed that transcripts from more than 60% of 3R-MYB genes undergo AS. AS could regulate transcriptional activity for some of the plant 3R-MYBs by generating different regulatory motifs. The 3R-MYB genes of all subgroups appear to be enriched for Mitosis-Specific Activator element core sequences within their upstream promoter region, which suggests a functional involvement in cell cycle. Notably, expression of 3R-MYB genes from different species exhibits differential regulation under various abiotic stresses. These data suggest that the plant 3R-MYBs function in both cell cycle regulation and abiotic stress response, which may contribute to the adaptation of plants to a sessile lifestyle.
Core Ideas
Association analyses of cold‐tolerance traits of white clover revealed 17 quantitative loci
Genomic tetraploid parameterization allowed description of population
Genomic tetraploid ...parameterization improved QTL detection in this polyploidy species
WSCdr found to be important physiological mechanism conferring cold tolerance
Four candidate genes discovered for WSCdr
Significant phenotypic variation explained by markers found associated with traits
MAS for some tolerance traits now seems possible
White clover (Trifolium repens L.) is the most important grazing perennial forage legume in temperate climates. However, its limited capacity to survive and restore growth after low temperatures during winter constrains the productivity and wide adoption of the crop. Despite the importance of cold tolerance for white clover cultivar development, the genetic basis of this trait remains largely unknown. Hence, in this study, we performed the first genome‐wide association study (GWAS) analyses in white clover to identify quantitative trait loci (QTL) for cold‐tolerance‐related traits. Seeds from 192 divergent genotypes from six populations in the Patagonia region of South America were collected and seed‐derived plants were further clonally propagated. Clonal trials were established in three locations representing temperature gradient associated with elevation. Given the allotetraploid nature of the white clover genome, distinct genetic models (diploid and tetraploid) were tested. Only the tetraploid parameterization was able to detect the 53 loci associated with cold‐tolerance traits. Out of the 53 single nucleotide polymorphism (SNP) trait associations, 17 controlled more than one trait or were stable across multiple sites. This work represents the first report of QTL for cold‐tolerance‐related traits, providing insights into its genetic basis and candidate genomic regions for further functional validation studies.
The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer's disease and has been implicated as a suppressor of melanoma progression. The APOE ...germline genotype predicts human melanoma outcomes, with APOE4 and APOE2 allele carriers exhibiting prolonged and reduced survival, respectively, relative to APOE3 homozygotes. While the APOE4 variant was recently shown to suppress melanoma progression by enhancing antitumor immunity, further work is needed to fully characterize the melanoma cell-intrinsic effects of APOE variants on cancer progression. Using a genetically engineered mouse model, we showed that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner. The low-density lipoprotein receptor-related protein 1 (LRP1) receptor mediated the cell-intrinsic effects of APOE variants on melanoma progression. Protein synthesis was a tumor cell-intrinsic process differentially modulated by APOE variants, with APOE2 promoting translation via LRP1. These findings reveal a gain-of-function role for the APOE2 variant in melanoma progression, which may aid in predicting melanoma patient outcomes and understanding the protective effect of APOE2 in Alzheimer's disease.
APOE germline variants impact melanoma progression through disparate mechanisms, such as the protein synthesis-promoting function of the APOE2 variant, indicating that germline genetic variants are causal contributors to metastatic outcomes.
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