Localized mRNA translation is a biological process that allows mRNA to be translated on-site, which is proposed to provide fine control in protein regulation, both spatially and temporally within a cell. We recently reported that Vasa, an RNA-helicase, is a promising factor that appears to regulate this process on the spindle during the embryonic development of the sea urchin, yet the detailed roles and functional mechanisms of Vasa in this process are still largely unknown. In this review article, to elucidate (...) these remaining questions, we first summarize the prior knowledge and our recent findings in the area of Vasa research and further discuss how Vasa may function in localized mRNA translation, contributing to efficient protein regulation during rapid embryogenesis and cancer cell regulation. (shrink)

Neddylation, a ubiquitylation-like post-translational modification, is catalyzed by a cascade composed of three enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase with cullins as physiological substrates. Specifically, neddylation E2 UBE2M couples with E3 RBX1 to neddylate cullins 1–4, whereas neddylation E2 UBE2F couples with E3 RBX2/SAG to neddylate cullin 5, leading to activation of CRL1-4 (Cullin-RING ligases 1–4) and CRL5, respectively. While over-activation of the neddylation-CRLs axis occurs frequently in many human cancers, how neddylation-CRLs regulate the function of (...) immune cells, particularly Treg cells was previously unknown. To this end, we recently performed Treg selective knockout of two neddylation E2s and two E3s, individually, driven by Foxp3-Cre, and found that while the Ube2f-Sag E2/E3 pair plays a minimal role, if any, the Ube2m-Rbx1 pair is essential for the maintenance of Treg functionality, since their deletion triggers robust inflammatory response with autoimmune phenotypes. Milder phenotype severity upon Treg KO of upstream Ube2m than that of downstream Rbx1 strongly suggested that Rbx1 regulates Treg function in a manner dependent and independent of neddylation. (shrink)

Since the 16th century, assays and screens have been essential for scientific investigation. However, most methods could be significantly improved, especially in accuracy, scalability, and often lack adequate comparisons to negative controls. There is a lack of consistency in distinguishing assays, in which accuracy is the main goal, from screens, in which scalability is prioritized over accuracy. We dissected and modernized the original definitions of assays and screens based upon recent developments and the conceptual framework of the original definitions. All (...) methods have three components: design/measurement, performance, and interpretation. We propose a model of method development in which reproducible observations become new methods, initially assessed by sensitivity. Further development can proceed along a path to either screens or assays. The screen path focuses on scalability first, but can later prioritize analysis of negatives. Alternatively, the assay path first compares results to negative controls, assessing specificity and accuracy, later adding scalability. Both pathways converge on a high-accuracy and throughput (HAT) assay, like next generation sequencing, which we suggest should be the ultimate goal of all testing methods. Our model will help scientists better select among available methods, as well as improve existing methods, expanding their impact on science. (shrink)

Osteoporosis (OP) is a bone disease which affects a number of post-menopausal females and puts many at risk for fractures. A large number of patients are taking bisphosphonates (BPs) to treat their OP and a rare complication is the development of atypical femoral fractures (AFF). No real explanations for the mechanisms underlying the basis for development of where AFF develop while on BPs has emerged. The present hypothesis will discuss the possibility that part of the risk for an AFF is (...) a secondary effect of BPs on a subset of vascular cells in a genetically at-risk population, leading to localized deregulation of the endothelial cell (EC)-bone cell-matrix units in nutrient channels/canals of the femur and increased risk for AFF. This concept of targeting ECs is consistent with location of AFF in the femur, the bilateral risk for occurrence of AFF, and the requirement for long term exposure to the drugs. (shrink)

Which sounds composed the first spoken languages? Archetypal sounds are not phylogenetically or archeologically recoverable, but comparative linguistics and primatology provide an alternative approach. Labial articulations are the most common speech sound, being virtually universal across the world's languages. Of all labials, the plosive ‘p’ sound, as in ‘Pablo Picasso’, transcribed /p/, is the most predominant voiceless sound globally and one of the first sounds to emerge in human infant canonical babbling. Global omnipresence and ontogenetic precocity imply that /p/-like sounds (...) could predate the first major linguistic diversification event(s) in humans. Indeed, great ape vocal data support this view, namely, the only cultural sound shared across all great ape genera is articulatorily homologous to a rolling or trilled /p/, the ‘raspberry’. /p/-like labial sounds represent an ‘articulatory attractor’ among living hominids and are likely among the oldest phonological features to have ever emerged in linguistic systems. (shrink)

Error-free genome duplication and accurate cell division are critical for cell survival. In all three domains of life, bacteria, archaea, and eukaryotes, initiator proteins bind replication origins in an ATP-dependent manner, play critical roles in replisome assembly, and coordinate cell-cycle regulation. We discuss how the eukaryotic initiator, Origin recognition complex (ORC), coordinates different events during the cell cycle. We propose that ORC is the maestro driving the orchestra to coordinately perform the musical pieces of replication, chromatin organization, and repair.

Rejuvenation of cells by reprogramming toward the pluripotent state raises increasing attention. In fact, generation of induced pluripotent stem cells (iPSCs) completely reverses age-associated molecular features, including elongation of telomeres, resetting of epigenetic clocks and age-associated transcriptomic changes, and even evasion of replicative senescence. However, reprogramming into iPSCs also entails complete de-differentiation with loss of cellular identity, as well as the risk of teratoma formation in anti-ageing treatment paradigms. Recent studies indicate that partial reprogramming by limited exposure to reprogramming factors (...) can reset epigenetic ageing clocks while maintaining cellular identity. So far, there is no commonly accepted definition of partial reprogramming, which is alternatively called interrupted reprogramming, and it remains to be elucidated how the process can be controlled and if it resembles a stable intermediate state. In this review, we discuss if the rejuvenation program can be uncoupled from the pluripotency program or if ageing and cell fate determination are inextricably linked. Alternative rejuvenation approaches with reprogramming into a pluripotent state, partial reprogramming, transdifferentiation, and the possibility of selective resetting of cellular clocks are also discussed. (shrink)

Mediator is a coregulatory complex that plays essential roles in multiple processes of transcription regulation. One of the human Mediator subunits, MED26, has a role in recruitment of the super elongation complex (SEC) to polyadenylated genes and little elongation complex (LEC) to non-polyadenylated genes, including small nuclear RNAs (snRNAs) and replication-dependent histone (RDH) genes. MED26-containing Mediator plays a role in 3′ Pol II pausing at the proximal region of transcript end sites in RDH genes through recruitment of Cajal bodies (CBs) (...) to histone locus bodies (HLBs). This finding suggests that Mediator is involved in the association of CBs with HLBs to facilitate 3′ Pol II pausing and subsequent 3′-end processing by supplying 3′-end processing factors from CBs. Thus, we argue the possibility that Mediator is involved in the organization of nuclear bodies to orchestrate multiple processes of gene transcription. (shrink)

Unraveling molecular and functional heterogeneity of niche cells within the developing endoderm could resolve mechanisms of tissue formation and maturation. Here, we discuss current unknowns in molecular mechanisms underlying key developmental events in pancreatic islet and intestinal epithelial formation. Recent breakthroughs in single-cell and spatial transcriptomics, paralleled with functional studies in vitro, reveal that specialized mesenchymal subtypes drive the formation and maturation of pancreatic endocrine cells and islets via local interactions with epithelium, neurons, and microvessels. Analogous to this, distinct intestinal (...) niche cells regulate both epithelial development and homeostasis throughout life. We propose how this knowledge can be used to progress research in the human context using pluripotent stem cell-derived multilineage organoids. Overall, understanding the interactions between the multitude of microenvironmental cells and how they drive tissue development and function could help us make more therapeutically relevant in vitro models. (shrink)

Integrative mobile genetic elements (MGEs), such as transposons and insertion sequences, propagate within bacterial genomes, but persistence times in individual lineages are short. For long-term survival, MGEs must continuously invade new hosts by horizontal transfer. Theoretically, MGEs that persist for millions of years in single lineages, and are thus subject to vertical inheritance, should not exist. Here we draw attention to an exception – a class of MGE termed REPIN. REPINs are non-autonomous MGEs whose duplication depends on non-jumping RAYT transposases. (...) Comparisons of REPINs and typical MGEs show that replication rates of REPINs are orders of magnitude lower, REPIN population size fluctuations correlate with changes in available genome space, REPIN conservation depends on RAYT function, and REPIN diversity accumulates within host lineages. These data lead to the hypothesis that REPINs form enduring, beneficial associations with eubacterial chromosomes. Given replicative nesting, our hypothesis predicts conflicts arising from the diverging effects of selection acting simultaneously on REPINs and host genomes. Evidence in support comes from patterns of REPIN abundance and diversity in two distantly related bacterial species. Together this bolsters the conclusion that REPINs are the genetic counterpart of mutualistic endosymbiotic bacteria. (shrink)

Broad-complex, Tramtrack, and Bric-à-brac/poxvirus and zinc finger (BTB/POZ) is a conserved domain found in many eukaryotic proteins with diverse cellular functions. Recent studies revealed its importance in multiple developmental processes as well as in the onset and progression of oncological diseases. Most BTB domains can form multimers and selectively interact with non-BTB proteins. Structural studies of BTB domains delineated the presence of different interfaces involved in various interactions mediated by BTBs and provided a basis for the specific inhibition of distinct (...) protein-interaction interfaces. BTB domains originated early in eukaryotic evolution and progressively adapted their structural elements to perform distinct functions. In this review, we summarize and discuss the structural principles of protein-protein interactions mediated by BTB domains based on the recently published structural data and advances in protein modeling. We propose an update to the structure-based classification of BTB domain families and discuss their evolutionary interconnections. (shrink)

Biomedical and social scientists are increasingly calling the biological sex into question, arguing that sex is a graded spectrum rather than a binary trait. Leading science journals have been adopting this relativist view, thereby opposing fundamental biological facts. While we fully endorse efforts to create a more inclusive environment for gender-diverse people, this does not require denying biological sex. On the contrary, the rejection of biological sex seems to be based on a lack of knowledge about evolution and it champions (...) species chauvinism, inasmuch as it imposes human identity notions on millions of other species. We argue that the biological definition of the sexes remains central to recognising the diversity of life. Humans with their unique combination of biological sex and gender are different from non-human animals and plants in this respect. Denying the concept of biological sex, for whatever cause, ultimately erodes scientific progress and may open the flood gates to “alternative truths.”. (shrink)

The release of AlphaFold2 (AF2), a deep-learning-aided, open-source protein structure prediction program, from DeepMind, opened a new era of molecular biology. The astonishing improvement in the accuracy of the structure predictions provides the opportunity to characterize protein systems from uncultured Asgard archaea, key organisms in evolutionary biology. Despite the accumulation in metagenomics-derived Asgard archaea eukaryotic-like protein sequences, limited structural and biochemical information have restricted the insight in their potential functions. In this review, we focus on profilin, an actin-dynamics regulating protein, (...) which in eukaryotes, modulates actin polymerization through (1) direct actin interaction, (2) polyproline binding, and (3) phospholipid binding. We assess AF2-predicted profilin structures in their potential abilities to participate in these activities. We demonstrate that AF2 is a powerful new tool for understanding the emergence of biological functional traits in evolution. (shrink)

Transfer RNAs (tRNAs) represent the most abundant class of RNA molecules in the cell and are key players during protein synthesis and cellular homeostasis. Aberrations in the extensive tRNA biogenesis pathways lead to severe neurological disorders in humans. Mutations in the tRNA splicing endonuclease (TSEN) and its associated RNA kinase cleavage factor polyribonucleotide kinase subunit 1 (CLP1) cause pontocerebellar hypoplasia (PCH), a heterogeneous group of neurodegenerative disorders, that manifest as underdevelopment of specific brain regions typically accompanied by microcephaly, profound motor (...) impairments, and child mortality. Recently, we demonstrated that mutations leading to specific PCH subtypes destabilize TSEN in vitro and cause imbalances of immature to mature tRNA ratios in patient-derived cells. However, how tRNA processing defects translate to disease on a systems level has not been understood. Recent findings suggested that other cellular processes may be affected by mutations in TSEN/CLP1 and obscure the molecular mechanisms of PCH emergence. Here, we review PCH disease models linked to the TSEN/CLP1 machinery and discuss future directions to study neuropathogenesis. (shrink)

Recent years have seen an emergence of the field of comparative cancer genomics. However, the advancements in this field are held back by the hesitation to use knowledge obtained from human studies to study cancer in other animals, and vice versa. Since cancer is an ancient disease that arose with multicellularity, oncogenes and tumour-suppressor genes are amongst the oldest gene classes, shared by most animal species. Acknowledging that other animals are, in terms of cancer genetics, ecology, and evolution, rather similar (...) to humans, creates huge potential for advancing the fields of human and animal oncology, but also biodiversity conservation. Also see the video abstract here: https://youtu.be/UFqyMx5HETY. (shrink)

Classic genetics studies found that genomic imbalance caused by changing the dosage of part of the genome (aneuploidy) has more detrimental effects than altering the dosage of the whole genome (ploidy). Previous analysis revealed global modulation of gene expression triggered by aneuploidy across various species, including maize (Zea mays), Arabidopsis, yeast, mammals, etc. Plant microRNAs (miRNAs) are a class of 20- to 24-nt endogenous small noncoding RNAs that carry out post-transcriptional gene expression regulation. That miRNAs and their putative targets are (...) preferentially retained as duplicates after whole-genome duplication, as are many transcription factors and signaling components, indicates miRNAs are likely to be dosage-sensitive and potentially involved in genomic balance networks. This review addresses the following questions regarding the role of miRNAs in genomic imbalance. (1) How do aneuploidy and polyploidy impact the expression of miRNAs? (2) Do miRNAs play a regulatory role in modulating the expression of their targets under genomic imbalance? (shrink)

In contrast to bilaterian animals, non-bilaterian mitochondrial genomes contain atypical genes, often attributed to horizontal gene transfer (HGT) as an ad hoc explanation. Although prevalent in plants, HGT into animal mitochondrial genomes is rare, lacking suitable explanatory models for their occurrence. HGT of the mismatch DNA repair gene (mtMutS) from giant viruses to octocoral (soft corals and their kin) mitochondrial genomes provides a model for how barriers to HGT to animal mitochondria may be overcome. A review of the available literature (...) suggests that this HGT was mediated by an alveolate endosymbiont infected with a lysogenic phycodnavirus that enabled insertion of the homing endonuclease containing mtMutS into octocoral mitochondrial genomes. We posit that homing endonuclease domains and similar selfish elements play a crucial role in such inter-domain gene transfers. Understanding the role of selfish genetic elements in HGT has the potential to aid development of tools for manipulating animal mitochondrial DNA. (shrink)

The molecular mechanism of temperature-dependent sex determination (TSD) is a long-standing mystery. How is the thermal signal sensed, captured and transduced to regulate key sex genes? Although there is compelling evidence for pathways via which cells capture the temperature signal, there is no known mechanism by which cells transduce those thermal signals to affect gene expression. Here we propose a novel hypothesis we call 3D-TSD (the three dimensions of thermolabile sex determination). We postulate that the genome has capacity to remodel (...) in response to temperature by changing 3D chromatin conformation, perhaps via temperature-sensitive transcriptional condensates. This could rewire enhancer–promoter interactions to alter the expression of key sex-determining genes. This hypothesis can accommodate monogenic or multigenic thermolabile sex-determining systems, and could be combined with upstream thermal sensing and transduction to the epigenome to commit gonadal fate. (shrink)

We hypothesize that as one of the most consequential events in evolution, primary endosymbiosis accelerates lineage divergence, a process we refer to as the endosymbiotic ratchet. Our proposal is supported by recent work on the photosynthetic amoeba, Paulinella, that underwent primary plastid endosymbiosis about 124 Mya. This amoeba model allows us to explore the early impacts of photosynthetic organelle (plastid) origin on the host lineage. The current data point to a central role for effective population size (Ne) in accelerating divergence (...) post-endosymbiosis due to limits to dispersal and reproductive isolation that reduce Ne, leading to local adaptation. We posit that isolated populations exploit different strategies and behaviors and assort themselves in non-overlapping niches to minimize competition during the early, rapid evolutionary phase of organelle integration. The endosymbiotic ratchet provides a general framework for interpreting post-endosymbiosis lineage evolution that is driven by disruptive selection and demographic and population shifts. Also see the video abstract here: https://youtu.be/gYXrFM6Zz6Q. (shrink)

Cancers often express hundreds of genes otherwise specific to germ cells, the germline/cancer (GC) genes. Here, we present and discuss the hypothesis that activation of a “germline program” promotes cancer cell malignancy. We do so by proposing four hallmark processes of the germline: meiosis, epigenetic plasticity, migration, and metabolic plasticity. Together, these hallmarks enable replicative immortality of germ cells as well as cancer cells. Especially meiotic genes are frequently expressed in cancer, implying that genes unique to meiosis may play a (...) role in oncogenesis. Because GC genes are not expressed in healthy somatic tissues, they form an appealing source of specific treatment targets with limited side effects besides infertility. Although it is still unclear why germ cell specific genes are so abundantly expressed in cancer, from our hypothesis it follows that the germline's reproductive program is intrinsic to cancer development. (shrink)

Almost 40 years since the discovery of microtubule dynamic instability, the molecular mechanisms underlying microtubule dynamics remain an area of intense research interest. The “standard model” of microtubule dynamics implicates a “cap” of GTP-bound tubulin dimers at the growing microtubule end as the main determinant of microtubule stability. Loss of the GTP-cap leads to microtubule “catastrophe,” a switch-like transition from microtubule growth to shrinkage. However, recent studies, using biochemical in vitro reconstitution, cryo-EM, and computational modeling approaches, challenge the simple GTP-cap (...) model. Instead, a new perspective on the mechanisms of microtubule dynamics is emerging. In this view, highly dynamic transitions between different structural conformations of the growing microtubule end – which may or may not be directly linked to the nucleotide content at the microtubule end – ultimately drive microtubule catastrophe. (shrink)

With the potential to process the world's agricultural and food waste, provide sustainable fodder for livestock, aquaculture, and pet animals, as well as act as a source of novel biomolecules, the black soldier fly, Hermetia illucens, has been launched into the leading position within the insects as feed industry. Fulfilment of these goals, however, requires mass-rearing facilities to have a steady supply of neonate larvae, which in-turn requires an efficient mating process to yield fertile eggs; yet, little is known about (...) adult reproductive behavior, nor what physiological factors lead to its emergence. Moreover, fertile egg production tends to be highly variable in colony. Therefore, this review brings together what is currently known of the organismal biology of H. illucens, compiling information on adult morphology, physiology, biogeography, genomics, and behavioral ecology. As a holistic synthesis, it highlights several directions of interest for research to follow. (shrink)

The initial relationships between organisms leading to endosymbiosis and the first eukaryote are currently a topic of hot debate. Here, I present a theory that offers a gradual scenario in which the origins of phagocytosis and mitochondria are intertwined in such a way that the evolution of one would not be possible without the other. In this scenario, the premitochondrial bacterial symbiont became initially associated with a protophagocytic host on the basis of cooperation to kill prey with symbiont-produced toxins and (...) reactive oxygen species (ROS). Subsequently, the cooperation was focused on the digestion stage, through the acidification of the protophagocytic cavities via exportation of protons produced by the aerobic respiration of the symbiont. The host gained an improved phagocytic capacity and the symbiont received organic compounds from prey. As the host gradually lost its membrane energetics to develop lysosomal digestion, respiration was centralized in the premitochondrial symbiont for energy production for the consortium. (shrink)

While heredity is predominantly controlled by what deoxyribonucleic acid (DNA) sequences are passed from parents to their offspring, a small but growing number of traits have been shown to be regulated in part by the non-genetic inheritance of information. Transgenerational epigenetic inheritance is defined as heritable information passed from parents to their offspring without changing the DNA sequence. Work of the past seven decades has transitioned what was previously viewed as rare phenomenology, into well-established paradigms by which numerous traits can (...) be modulated. For the most part, studies in model organisms have correlated transgenerational epigenetic inheritance phenotypes with changes in epigenetic modifications. The next steps for this field will entail transitioning from correlative studies to causal ones. Here, we delineate the major molecules that have been implicated in transgenerational epigenetic inheritance in both mammalian and non-mammalian models, speculate on additional molecules that could be involved, and highlight some of the tools which might help transition this field from correlation to causation. (shrink)

All animals have evolved solutions to manage their genomes, enabling the efficient organization of meters of DNA strands in the nucleus and allowing for nuanced regulation of gene expression while keeping transposable elements suppressed. Epigenetic modifications are central to accomplishing all these. Recent advances in sequencing technologies and the development of techniques that profile epigenetic marks and chromatin accessibility using reagents that can be used in any species has catapulted epigenomic studies in diverse animal species, shedding light on the multitude (...) of epigenomic mechanisms utilized across the evolutionary tree. Now, comparative epigenomics is a rapidly growing field that is uncovering mechanistic aspects of epigenetic modifications and chromatin organization in non-model invertebrates, ranging from octopus to sponges. This review puts recent discoveries in the epigenetics of non-model invertebrates in historical context, and describes new insight into the patterning and functions of DNA methylation and other highly conserved epigenetic modifications. (shrink)

Small tandem DNA duplications in the range of 15 to 300 base-pairs play an important role in the aetiology of human disease and contribute to genome diversity. Here, we discuss different proposed mechanisms for their occurrence and argue that this type of structural variation mainly results from mutagenic repair of chromosomal breaks. This hypothesis is supported by both bioinformatical analysis of insertions occurring in the genome of different species and disease alleles, as well as by CRISPR/Cas9-based experimental data from different (...) model systems. Recent work points to fill-in synthesis at double-stranded DNA breaks with complementary sequences, regulated by end-joining mechanisms, to account for small tandem duplications. We will review the prevalence of small tandem duplications in the population, and we will speculate on the potential sources of DNA damage that could give rise to this mutational signature. With the development of novel algorithms to analyse sequencing data, small tandem duplications are now more frequently detected in the human genome and identified as oncogenic gain-of-function mutations. Understanding their origin could lead to optimized treatment regimens to prevent therapy-induced activation of oncogenes and might expose novel vulnerabilities in cancer. (shrink)

Recently discovered transcription-independent features of p53 involve the choice of DNA damage repair pathway after PARylation, and p53's complex formation with phosphoinositide lipids, PI(4,5)P2. PARylation-mediated rapid accumulation of p53 at DNA damage sites is linked to the recruitment of downstream repair factors and tumor suppression. This links p53's capability to sense damaged DNA in vitro and its relevant functions in cells. Further, PI(4,5)P2 rapidly accumulates at damage sites like p53 and complexes with p53, while it is required for ATR recruitment. (...) These findings help explain how p53 and PI(4,5)P2 maintain genome stability by directing DNA repair pathway choice. Additionally, there is a strong correlation between p53 sequence homology, genome mutation rates as well as lifespans across various mammalian species. Further investigation is required to better understand the connections between genome stability, tumor suppression, longevity and the transcriptional-independent function of p53. (shrink)