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  • Raw Genomic Data: Storage, Access, and Sharing
    Trends Genet. (IF 10.844) Pub Date : 2017-11-10
    Mahsa Shabani, Danya Vears, Pascal Borry

    Patients are increasingly being encouraged and supported to access and control their own medical and genomic data. We argue that well-established and transparent raw genomic data retention and returning policies are imperative to enable patients to practice their rights to access and control raw data.

  • Intergenerational Transmission of Gene Regulatory Information in Caenorhabditis elegans
    Trends Genet. (IF 10.844) Pub Date : 2017-11-02
    Olga Minkina, Craig P. Hunter

    Epigenetic mechanisms can stably maintain gene expression states even after the initiating conditions have changed. Often epigenetic information is transmitted only to daughter cells, but evidence is emerging, in both vertebrate and invertebrate systems, for transgenerational epigenetic inheritance (TEI), the transmission of epigenetic gene regulatory information across generations. Each new description of TEI helps uncover the properties, molecular mechanisms and biological roles for TEI. The nematode Caenorhabditis elegans has been particularly instrumental in the effort to understand TEI, as multiple environmental and genetic triggers can initiate an epigenetic signal that can alter the expression of both transgenes and endogenous loci. Here, we review recent studies of TEI in C. elegans.

  • Keeping Neurons Young and Foxy: FoxOs Promote Neuronal Plasticity
    Trends Genet. (IF 10.844) Pub Date : 2017-11-01
    Colleen N. McLaughlin, Heather T. Broihier

    Any adult who has tried to take up the piano or learn a new language is faced with the sobering realization that acquiring such skills is more challenging as an adult than as a child. Neuronal plasticity, or the malleability of brain circuits, declines with age. Young neurons tend to be more adaptable and can alter the size and strength of their connections more readily than can old neurons. Myriad circuit- and synapse-level mechanisms that shape plasticity have been identified. Yet, molecular mechanisms setting the overall competence of young neurons for distinct forms of plasticity remain largely obscure. Recent studies indicate evolutionarily conserved roles for FoxO proteins in establishing the capacity for cell-fate, morphological, and synaptic plasticity in neurons.

  • Faithful Artificial Chromosome Propagation Using Spermatogonial Stem Cells
    Trends Genet. (IF 10.844) Pub Date : 2017-10-26
    M. Yamada, M. Seandel

    Artificial chromosomes are useful in making functional vectors for very large genes, studying chromosome physiology, and modeling chromosomal disorders. Shinohara et al. have succeeded for the first time in creating transchromosomic mice by manipulating spermatogonial stem cells (SSCs), which exhibited superior chromosomal stability compared with embryonic stem cells (ESCs).

  • Functional Genomics of Host–Microbiome Interactions in Humans
    Trends Genet. (IF 10.844) Pub Date : 2017-10-26
    Francesca Luca, Sonia S. Kupfer, Dan Knights, Alexander Khoruts, Ran Blekhman

    The human microbiome has been linked to various host phenotypes and has been implicated in many complex human diseases. Recent genome-wide association studies (GWASs) have used microbiome variation as a complex trait and have uncovered human genetic variants that are associated with the microbiome. Here we summarize results from these studies and illustrate potential regulatory mechanisms by which host genetic variation can interact with microbiome composition. We argue that, similar to human GWASs, it is important to use functional genomics techniques to gain a mechanistic understanding of causal host–microbiome interactions and their role in human disease. We highlight experimental, functional, and computational genomics methodologies for the study of the genomic basis of host–microbiome interactions and describe how these approaches can be utilized to explain how human genetic variation can modulate the effects of the microbiome on the host.

  • Development and Evolution through the Lens of Global Gene Regulation
    Trends Genet. (IF 10.844) Pub Date : 2017-10-20
    Itai Yanai

    Evolution and development are two inherently intertwined processes. As the embryo develops it does so in ways that both reflect past constraints and bias the future evolution of the species. While research exploiting this insight typically studies individual genes, transcriptomic analyses have sparked a new wave of discoveries. In this opinion piece, I review the evidence arising from transcriptomics on the topics of the evolution of germ layers, the phylotypic stage, and developmental constraints. The spatiotemporal pattern of gene expression across germ layers provides evidence that the endoderm was the first germ layer to evolve. Comparing transcriptome dynamics throughout developmental time across distant species reveals a mid-developmental transition under strong developmental constraints. These studies highlight the efficiency of exploratory data analysis using computational tools and comparative approaches for discovery.

  • Choosing the Active X: The Human Version of X Inactivation
    Trends Genet. (IF 10.844) Pub Date : 2017-10-05
    Barbara R. Migeon

    Humans and rodents differ in how they carry out X inactivation (XI), the mammalian method to compensate for the different number of X chromosomes in males and females. Evolutionary changes in staging embryogenesis and in mutations within the XI center alter the process among mammals. The mouse model of XI is predicated on X counting and subsequently choosing the X to ‘inactivate’. However, new evidence suggests that humans initiate XI by protecting one X in both sexes from inactivation by XIST, the noncoding RNA that silences the inactive X. This opinion article explores the question of how the active X is protected from silencing by its own Xist locus, and the possibility of different solutions for mouse and human.

  • Caenorhabditis elegans Dosage Compensation: Insights into Condensin-Mediated Gene Regulation
    Trends Genet. (IF 10.844) Pub Date : 2017-10-13
    Sarah Elizabeth Albritton, Sevinç Ercan

    Recent work demonstrating the role of chromosome organization in transcriptional regulation has sparked substantial interest in the molecular mechanisms that control chromosome structure. Condensin, an evolutionarily conserved multisubunit protein complex, is essential for chromosome condensation during cell division and functions in regulating gene expression during interphase. In Caenorhabditis elegans, a specialized condensin forms the core of the dosage compensation complex (DCC), which specifically binds to and represses transcription from the hermaphrodite X chromosomes. DCC serves as a clear paradigm for addressing how condensins target large chromosomal domains and how they function to regulate chromosome structure and transcription. Here, we discuss recent research on C. elegans DCC in the context of canonical condensin mechanisms as have been studied in various organisms.

  • Tag team: Roles of miRNAs and Proteolytic Regulators in Ensuring Robust Gene Expression Dynamics
    Trends Genet. (IF 10.844) Pub Date : 2017-10-13
    Benjamin P. Weaver, Min Han

    Lack of prominent developmental defects arising from loss of many individual miRNAs is consistent with the observations of collaborative networks between miRNAs and roles for miRNAs in regulating stress responses. However, these characteristics may only partially explain the seemingly nonessential nature of many miRNAs. Non-miRNA gene expression regulatory mechanisms also collaborate with miRNA-induced silencing complex (miRISC) to support robust gene expression dynamics. Genetic enhancer screens have revealed roles of miRNAs and other gene repressive mechanisms in development or other cellular processes that were masked by genetic redundancy. Besides discussing the breadth of the non-miRNA genes, we use LIN-28 as an example to illustrate how distinct regulatory systems, including miRNAs and multiple protein stability mechanisms, work at different levels to target expression of a given gene and provide tissue-specific and stage-specific regulation of gene expression.

  • Arresting Evolution
    Trends Genet. (IF 10.844) Pub Date : 2017-10-10
    James J. Bull, Jeffrey E. Barrick

    Evolution in the form of selective breeding has long been harnessed as a useful tool by humans. However, rapid evolution can also be a danger to our health and a stumbling block for biotechnology. Unwanted evolution can underlie the emergence of drug and pesticide resistance, cancer, and weeds. It makes live vaccines and engineered cells inherently unreliable and unpredictable, and therefore potentially unsafe. Yet, there are strategies that have been and can possibly be used to stop or slow many types of evolution. We review and classify existing population genetics-inspired methods for arresting evolution. Then, we discuss how genome editing techniques enable a radically new set of approaches to limit evolution.

  • SAMHD1 Sheds Moonlight on DNA Double-Strand Break Repair
    Trends Genet. (IF 10.844) Pub Date : 2017-09-29
    Maria Jose Cabello-Lobato, Siyue Wang, Christine Katrin Schmidt

    SAMHD1 (sterile α motif and histidine (H) aspartate (D) domain-containing protein 1) is known for its antiviral activity of hydrolysing deoxynucleotides required for virus replication. Daddacha et al. identify a hydrolase-independent, moonlighting function of SAMHD1 that facilitates homologous recombination of DNA double-strand breaks (DSBs) by promoting recruitment of C-terminal binding protein interacting protein (CTIP), a DNA-end resection factor, to damaged DNA. These findings could benefit anticancer treatment.

  • Alternative Lengthening of Telomeres: DNA Repair Pathways Converge
    Trends Genet. (IF 10.844) Pub Date : 2017-09-29
    Alexander P. Sobinoff, Hilda A. Pickett

    Telomeres shorten during each cellular division, with cumulative attrition resulting in telomeric damage and replicative senescence. Bypass of replicative senescence precipitates catastrophic telomere shortening or crisis, and is characterized by widespread genomic instability. Activation of a telomere maintenance mechanism (TMM) is necessary to stabilise the genome and establish cellular immortality through the reconstitution of telomere capping function. The alternative lengthening of telomeres (ALT) pathway is a TMM frequently activated in tumors of mesenchymal or neuroepithelial origin. ALT is a homology-directed recombination-dependent replication pathway that utilizes telomeric templates for synthesis; however, its precise protein requirements have remained elusive. Recently, several developments have shed light on the DNA repair pathways that become engaged at ALT telomeres, implicating ALT telomeres as DNA repair hot spots. Here, we review recent discoveries regarding the ALT mechanism, and discuss how DNA repair pathways converge to maintain the length and functional integrity of telomeres in ALT cancers.

  • piRNA Biogenesis in Drosophila melanogaster
    Trends Genet. (IF 10.844) Pub Date : 2017-09-27
    Xiawei Huang, Katalin Fejes Tóth, Alexei A. Aravin

    The PIWI-interacting RNA (piRNA) pathway is a conserved defense system that protects the genome integrity of the animal germline from deleterious transposable elements. Targets of silencing are recognized by small noncoding piRNAs that are processed from long precursor molecules. Although piRNAs and other classes of small noncoding RNAs, such as miRNAs and small interfering (si)RNAs, interact with members of the same family of Argonaute (Ago) proteins and their function in target repression is similar, the biogenesis of piRNAs differs from those of the other two small RNAs. Recently, many aspects of piRNA biogenesis have been revealed in Drosophila melanogaster. In this review, we elaborate on piRNA biogenesis in Drosophila somatic and germline cells. We focus on the mechanisms by which piRNA precursor transcription is regulated and highlight recent work that has advanced our understanding of piRNA precursor processing to mature piRNAs. We finish by discussing current models to the still unresolved question of how piRNA precursors are selected and channeled into the processing machinery.

  • Gene Therapy with the Sleeping Beauty Transposon System
    Trends Genet. (IF 10.844) Pub Date : 2017-09-27
    Partow Kebriaei, Zsuzsanna Izsvák, Suneel A. Narayanavari, Harjeet Singh, Zoltán Ivics

    The widespread clinical implementation of gene therapy requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective, and economical manner. The latest generation of Sleeping Beauty (SB) transposo{ԌE{Ԍequirements, and may overcome limitations associated with viral gene transfer vectors and transient nonviral gene delivery approaches that are prevalent in ongoing clinical trials. The SB system enables high-level stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, thereby representing a highly attractive gene transfer strategy for clinical use. Here, we review the most important aspects of using SB for gene therapy, including vectorization as well as genomic integration features. We also illustrate the path to successful clinical implementation by highlighting the application of chimeric antigen receptor (CAR)-modified T cells in cancer immunotherapy.

  • Revisiting the Relationship between Transposable Elements and the Eukaryotic Stress Response
    Trends Genet. (IF 10.844) Pub Date : 2017-09-22
    Vivien Horváth, Miriam Merenciano, Josefa González

    A relationship between transposable elements (TEs) and the eukaryotic stress response was suggested in the first publications describing TEs. Since then, it has often been assumed that TEs are activated by stress, and that this activation is often beneficial for the organism. In recent years, the availability of new high-throughput experimental techniques has allowed further interrogation of the relationship between TEs and stress. By reviewing the recent literature, we conclude that although there is evidence for a beneficial effect of TE activation under stress conditions, the relationship between TEs and the eukaryotic stress response is quite complex.

  • Stay Connected: A Germ Cell Strategy
    Trends Genet. (IF 10.844) Pub Date : 2017-09-22
    Kevin Lu, Lindy Jensen, Lei Lei, Yukiko M. Yamashita

    Germ cells develop as a cyst of interconnected sibling cells in a broad range of organisms in both sexes. A well-established function of intercellular connectivity is to transport cytoplasmic materials from ‘nurse’ cells to oocytes, a critical process for developing functional oocytes in ovaries of many species. However, there are situations where connectivity exists without a nursing mechanism, and the biological meaning of such connectivity remains obscure. In this review, we summarize current knowledge on the formation of intercellular connectivity, and discuss its meaning by visiting multiple examples of germ cell connectivity observed in evolutionarily distant species.

  • The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian Evolution
    Trends Genet. (IF 10.844) Pub Date : 2017-09-19
    Peng Yang, Yixuan Wang, Todd S. Macfarlan

    Kruppel-associated box zinc-finger proteins (KRAB-ZFPs) make up the largest family of transcription factors in humans. These proteins emerged in the last common ancestor of coelacanth and tetrapods, and have expanded and diversified in the mammalian lineage. Although their mechanism of transcriptional repression has been well studied for over a decade, the DNA-binding activities and the biological functions of these proteins have been largely unexplored. Recent large-scale ChIP-seq studies and loss-of-function experiments have revealed that KRAB-ZFPs play a major role in the recognition and transcriptional silencing of transposable elements (TEs), consistent with an ‘arms race model’ of KRAB-ZFP evolution against invading TEs. However, this model is insufficient to explain the evolution of many KRAB-ZFPs that appear to domesticate TEs for novel host functions. We highlight some of the mammalian regulatory innovations driven by specific KRAB-ZFPs, including genomic imprinting, meiotic recombination hotspot choice, and placental growth.

  • Epithelial-to-Mesenchymal Transition: Epigenetic Reprogramming Driving Cellular Plasticity
    Trends Genet. (IF 10.844) Pub Date : 2017-09-14
    Nicolas Skrypek, Steven Goossens, Eva De Smedt, Niels Vandamme, Geert Berx

    Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells lose their junctions and polarity to gain a motile mesenchymal phenotype. EMT is essential during embryogenesis and adult physiological processes like wound healing, but is aberrantly activated in pathological conditions like fibrosis and cancer. A series of transcription factors (EMT-inducing transcription factor; EMT-TF) regulate the induction of EMT by repressing the transcription of epithelial genes while activating mesenchymal genes through mechanisms still debated. The nuclear interaction of EMT-TFs with larger protein complexes involved in epigenetic genome modulation has attracted recent attention to explain functions of EMT-TFs during reprogramming and cellular differentiation. In this review, we discuss recent advances in understanding the interplay between epigenetic regulators and EMT transcription factors and how these findings could be used to establish new therapeutic approaches to tackle EMT-related diseases.

  • Playing Well with Others: Extrinsic Cues Regulate Neural Progenitor Temporal Identity to Generate Neuronal Diversity
    Trends Genet. (IF 10.844) Pub Date : 2017-09-09
    Mubarak Hussain Syed, Brandon Mark, Chris Q. Doe

    During neurogenesis, vertebrate and Drosophila progenitors change over time as they generate a diverse population of neurons and glia. Vertebrate neural progenitors have long been known to use both progenitor-intrinsic and progenitor-extrinsic cues to regulate temporal patterning. In contrast, virtually all temporal patterning mechanisms discovered in Drosophila neural progenitors (neuroblasts) involve progenitor-intrinsic temporal transcription factor cascades. Recent results, however, have revealed several extrinsic pathways that regulate Drosophila neuroblast temporal patterning: nutritional cues regulate the timing of neuroblast proliferation/quiescence and a steroid hormone cue that is required for temporal transcription factor expression. Here, we discuss newly discovered extrinsic cues regulating neural progenitor temporal identity in Drosophila, highlight conserved mechanisms, and raise open questions for the future.

  • Transposons As Tools for Functional Genomics in Vertebrate Models
    Trends Genet. (IF 10.844) Pub Date : 2017-09-06
    Koichi Kawakami, David A. Largaespada, Zoltán Ivics

    Genetic tools and mutagenesis strategies based on transposable elements are currently under development with a vision to link primary DNA sequence information to gene functions in vertebrate models. By virtue of their inherent capacity to insert into DNA, transposons can be developed into powerful tools for chromosomal manipulations. Transposon-based forward mutagenesis screens have numerous advantages including high throughput, easy identification of mutated alleles, and providing insight into genetic networks and pathways based on phenotypes. For example, the Sleeping Beauty transposon has become highly instrumental to induce tumors in experimental animals in a tissue-specific manner with the aim of uncovering the genetic basis of diverse cancers. Here, we describe a battery of mutagenic cassettes that can be applied in conjunction with transposon vectors to mutagenize genes, and highlight versatile experimental strategies for the generation of engineered chromosomes for loss-of-function as well as gain-of-function mutagenesis for functional gene annotation in vertebrate models, including zebrafish, mice, and rats.

  • Beyond Read-Counts: Ribo-seq Data Analysis to Understand the Functions of the Transcriptome
    Trends Genet. (IF 10.844) Pub Date : 2017-09-05
    Lorenzo Calviello, Uwe Ohler

    By mapping the positions of millions of translating ribosomes in the cell, ribosome profiling (Ribo-seq) has established its role as a powerful tool to study gene expression. Several laboratories have introduced modifications to the experimental protocol and expanded the repertoire of biochemical methods to study translation transcriptome-wide. However, the diversity of protocols highlights a need for standardization. At the same time, different computational analysis strategies have used Ribo-seq data to identify the set of translated sequences with high confidence. In this review we present an overview of such methodologies, outlining their assumptions, data requirements, and availability. At the interface between RNA and proteins, Ribo-seq can complement data from multiple omics approaches, zooming in on the central role of translation in the molecular cell.

  • Time to Go Bigger: Emerging Patterns in Macrogenetics
    Trends Genet. (IF 10.844) Pub Date : 2017-07-15
    Simon Blanchet, Jérôme G. Prunier, Hanne De Kort

    The increasing availability of large-scale and high-resolution data sets in population genetics is moving the field toward a novel research agenda. Here, we show how this shift toward macrogenetics should generate new perspectives and theories allowing the description, understanding, and prediction of patterns of genetic diversity at broad spatial, temporal, and taxonomic scales.

  • CRISPRing the Regulatory Genome, the Challenge Ahead
    Trends Genet. (IF 10.844) Pub Date : 2017-07-29
    Stephanie E. Sansbury, Katelyn M. Sweeney, Ophir Shalem

    CRISPR saturation mutagenesis has the potential to dissect the functional landscape of noncoding regions, but is highly susceptible to false discovery and misinterpretation. As recently published, Canver et al. have now taken the first steps towards addressing these issues by increasing screening resolution and analyzing the effects of off targets on hit calling.

  • Evolutionary Dynamics of Unreduced Gametes
    Trends Genet. (IF 10.844) Pub Date : 2017-07-18
    Julia M. Kreiner, Paul Kron, Brian C. Husband

    Unreduced gametes, which have the somatic (2n) chromosome number, are an important precursor to polyploid formation and apomixis. The product of irregularities in meiosis, 2n gametes are expected to be rare and deleterious in most natural populations, contrary to their wide taxonomic distribution and the prevalence of polyploidy. To better understand this discrepancy, we review contemporary evidence related to four aspects of 2n gamete dynamics in natural populations: (i) estimates of their frequency; (ii) their environmental and genetic determinants; (iii) adaptive and nonadaptive processes regulating their evolution; and (iv) factors regulating their union and production of polyploids in diploid populations. Aided by high-throughput methods of detection, these foci will advance our understanding of variation in 2n gametes within and among species, and their role in polyploid evolution.

  • Roles of RNase P and Its Subunits
    Trends Genet. (IF 10.844) Pub Date : 2017-07-08
    Nayef Jarrous

    Recent studies show that nuclear RNase P is linked to chromatin structure and function. Thus, variants of this ribonucleoprotein (RNP) complex bind to chromatin of small noncoding RNA genes; integrate into initiation complexes of RNA polymerase (Pol) III; repress histone H3.3 nucleosome deposition; control tRNA and PIWI-interacting RNA (piRNA) gene clusters for genome defense; and respond to Werner syndrome helicase (WRN)-related replication stress and DNA double-strand breaks (DSBs). Likewise, the related RNase MRP and RMRP-TERT (telomerase reverse transcriptase) are implicated in RNA-dependent RNA polymerization for chromatin silencing, whereas the telomerase carries out RNA-dependent DNA polymerization for telomere lengthening. Remarkably, the four RNPs share several protein subunits, including two Alba-like chromatin proteins that possess DEAD-like and ATPase motifs found in chromatin modifiers and remodelers. Based on available data, RNase P and related RNPs act in transition processes of DNA to RNA and vice versa and connect these processes to genome preservation, including replication, DNA repair, and chromatin remodeling.

  • High-Throughput Imaging for the Discovery of Cellular Mechanisms of Disease
    Trends Genet. (IF 10.844) Pub Date : 2017-07-18
    Gianluca Pegoraro, Tom Misteli

    High-throughput imaging (HTI) is a powerful tool in the discovery of cellular disease mechanisms. While traditional approaches to identify disease pathways often rely on knowledge of the causative genetic defect, HTI-based screens offer an unbiased discovery approach based on any morphological or functional defects of disease cells or tissues. In this review, we provide an overview of the use of HTI for the study of human disease mechanisms. We discuss key technical aspects of HTI and highlight representative examples of its practical applications for the discovery of molecular mechanisms of disease, focusing on infectious diseases and host–pathogen interactions, cancer, and rare genetic diseases. We also present some of the current challenges and possible solutions offered by novel cell culture systems and genome engineering approaches.

  • Left–Right Patterning: Breaking Symmetry to Asymmetric Morphogenesis
    Trends Genet. (IF 10.844) Pub Date : 2017-07-15
    Daniel T. Grimes, Rebecca D. Burdine

    Vertebrates exhibit striking left–right (L–R) asymmetries in the structure and position of the internal organs. Symmetry is broken by motile cilia-generated asymmetric fluid flow, resulting in a signaling cascade – the Nodal–Pitx2 pathway – being robustly established within mesodermal tissue on the left side only. This pathway impinges upon various organ primordia to instruct their side-specific development. Recently, progress has been made in understanding both the breaking of embryonic L–R symmetry and how the Nodal–Pitx2 pathway controls lateralized cell differentiation, migration, and other aspects of cell behavior, as well as tissue-level mechanisms, that drive asymmetries in organ formation. Proper execution of asymmetric organogenesis is critical to health, making furthering our understanding of L–R development an important concern.

  • Clinical Genomics in Inflammatory Bowel Disease
    Trends Genet. (IF 10.844) Pub Date : 2017-07-26
    Holm H. Uhlig, Aleixo M. Muise

    Genomic technologies inform the complex genetic basis of polygenic inflammatory bowel disease (IBD) as well as Mendelian disease-associated IBD. Aiming to diagnose patients that present with extreme phenotypes due to monogenic forms of IBD, genomics has progressed from ‘orphan disease’ research towards an integrated standard of clinical care. Advances in diagnostic clinical genomics are increasingly complemented by pathway-specific therapies that aim to correct the consequences of genetic defects. This highlights the exceptional potential for personalized precision medicine. IBD is nevertheless a challenging example for genomic medicine because the overall fraction of patients with Mendelian defects is low, the number of potential candidate genes is high, and interventional evidence is still emerging. We discuss requirements and prospects of explanatory and predictive clinical genomics in IBD.

  • Speech and Language: Translating the Genome
    Trends Genet. (IF 10.844) Pub Date : 2017-08-03
    Pelagia Deriziotis, Simon E. Fisher

    Investigation of the biological basis of human speech and language is being transformed by developments in molecular technologies, including high-throughput genotyping and next-generation sequencing of whole genomes. These advances are shedding new light on the genetic architecture underlying language-related disorders (speech apraxia, specific language impairment, developmental dyslexia) as well as that contributing to variation in relevant skills in the general population. We discuss how state-of-the-art methods are uncovering a range of genetic mechanisms, from rare mutations of large effect to common polymorphisms that increase risk in a subtle way, while converging on neurogenetic pathways that are shared between distinct disorders. We consider the future of the field, highlighting the unusual challenges and opportunities associated with studying genomics of language-related traits.

  • The New RNA World: Growing Evidence for Long Noncoding RNA Functionality
    Trends Genet. (IF 10.844) Pub Date : 2017-09-01
    Allison Jandura, Henry M. Krause

    The past decade has seen a major increase in the study of noncoding RNAs (ncRNAs). However, there remains a great deal of confusion and debate over the levels of functionality and mechanisms of action of the majority of these new transcripts. This Opinion article addresses several of these issues, focusing particularly on long ncRNAs (lncRNAs). We reemphasize the unique abilities of RNAs to form myriad structures as well as to interact with other RNAs, DNA, and proteins, which provide them with unique and powerful abilities. One of these, the ability to interact sequence specifically with DNA, has been largely overlooked. Accumulating evidence suggests that evolution has taken advantage of RNA’s properties via the rapid acquisition of new noncoding genes in testes, with subsequent gains of function in other tissues. This amplification process appears to be one of the major forces driving metazoan evolution and diversity.

  • Signaling and Gene Regulatory Networks in Mammalian Lens Development
    Trends Genet. (IF 10.844) Pub Date : 2017-08-31
    Ales Cvekl, Xin Zhang

    Ocular lens development represents an advantageous system in which to study regulatory mechanisms governing cell fate decisions, extracellular signaling, cell and tissue organization, and the underlying gene regulatory networks. Spatiotemporally regulated domains of BMP, FGF, and other signaling molecules in late gastrula–early neurula stage embryos generate the border region between the neural plate and non-neural ectoderm from which multiple cell types, including lens progenitor cells, emerge and undergo initial tissue formation. Extracellular signaling and DNA-binding transcription factors govern lens and optic cup morphogenesis. Pax6, c-Maf, Hsf4, Prox1, Sox1, and a few additional factors regulate the expression of the lens structural proteins, the crystallins. Extensive crosstalk between a diverse array of signaling pathways controls the complexity and order of lens morphogenetic processes and lens transparency.

  • Birth and Death of Histone mRNAs
    Trends Genet. (IF 10.844) Pub Date : 2017-08-31
    William F. Marzluff, Kaitlin P. Koreski

    In metazoans, histone mRNAs are not polyadenylated but end in a conserved stem-loop. Stem-loop binding protein (SLBP) binds to the stem-loop and is required for all steps in histone mRNA metabolism. The genes for the five histone proteins are linked. A histone locus body (HLB) forms at each histone gene locus. It contains factors essential for transcription and processing of histone mRNAs, and couples transcription and processing. The active form of U7 snRNP contains the HLB component FLASH (FLICE-associated huge protein), the histone cleavage complex (HCC), and a subset of polyadenylation factors including the endonuclease CPSF73. Histone mRNAs are rapidly degraded when DNA replication is inhibited by a 3′ to 5′ pathway that requires extensive uridylation of mRNA decay intermediates.

  • Regulatory Logic Underlying Diversification of the Neural Crest
    Trends Genet. (IF 10.844) Pub Date : 2017-08-26
    Megan L. Martik, Marianne E. Bronner

    The neural crest is a transient, multipotent population of cells that arises at the border of the developing nervous system. After closure of the neural tube, these cells undergo an epithelial-to-mesenchymal transition (EMT) to delaminate and migrate, often to distant locations in the embryo. Neural crest cells give rise to a diverse array of derivatives including neurons and glia of the peripheral nervous system, melanocytes, and bone and cartilage of the face. A gene regulatory network (GRN) controls the specification, delamination, migration, and differentiation of this fascinating cell type. With increasing technological advances, direct linkages within the neural crest GRN are being uncovered. The underlying circuitry is useful for understanding important topics such as reprogramming, evolution, and disease.

  • Transposable Element Domestication As an Adaptation to Evolutionary Conflicts
    Trends Genet. (IF 10.844) Pub Date : 2017-08-24
    Diwash Jangam, Cédric Feschotte, Esther Betrán

    Transposable elements (TEs) are selfish genetic units that typically encode proteins that enable their proliferation in the genome and spread across individual hosts. Here we review a growing number of studies that suggest that TE proteins have often been co-opted or ‘domesticated’ by their host as adaptations to a variety of evolutionary conflicts. In particular, TE-derived proteins have been recurrently repurposed as part of defense systems that protect prokaryotes and eukaryotes against the proliferation of infectious or invasive agents, including viruses and TEs themselves. We argue that the domestication of TE proteins may often be the only evolutionary path toward the mitigation of the cost incurred by their own selfish activities.

  • Circadian Clocks and Metabolism: Implications for Microbiome and Aging
    Trends Genet. (IF 10.844) Pub Date : 2017-08-24
    Georgios K. Paschos, Garret A. FitzGerald

    The circadian clock directs many aspects of metabolism, to separate in time opposing metabolic pathways and optimize metabolic efficiency. The master circadian clock of the suprachiasmatic nucleus synchronizes to light, while environmental cues such as temperature and feeding, out of phase with the light schedule, may synchronize peripheral clocks. This misalignment of central and peripheral clocks may be involved in the development of disease and the acceleration of aging, possibly in a gender-specific manner. Here we discuss the interplay between the circadian clock and metabolism, the importance of the microbiome, and how they relate to aging.

  • Multifarious Functions of the Fragile X Mental Retardation Protein
    Trends Genet. (IF 10.844) Pub Date : 2017-08-18
    Jenna K. Davis, Kendal Broadie

    Fragile X syndrome (FXS), a heritable intellectual and autism spectrum disorder (ASD), results from the loss of Fragile X mental retardation protein (FMRP). This neurodevelopmental disease state exhibits neural circuit hyperconnectivity and hyperexcitability. Canonically, FMRP functions as an mRNA-binding translation suppressor, but recent findings have enormously expanded its proposed roles. Although connections between burgeoning FMRP functions remain unknown, recent advances have extended understanding of its involvement in RNA, channel, and protein binding that modulate calcium signaling, activity-dependent critical period development, and the excitation–inhibition (E/I) neural circuitry balance. In this review, we contextualize 3 years of FXS model research. Future directions extrapolated from recent advances focus on discovering links between FMRP roles to determine whether FMRP has a multitude of unrelated functions or whether combinatorial mechanisms can explain its multifaceted existence.

  • Mobile Group II Introns as Ancestral Eukaryotic Elements
    Trends Genet. (IF 10.844) Pub Date : 2017-08-14
    Olga Novikova, Marlene Belfort

    The duality of group II introns, capable of carrying out both self-splicing and retromobility reactions, is hypothesized to have played a profound role in the evolution of eukaryotes. These introns likely provided the framework for the emergence of eukaryotic retroelements, spliceosomal introns and other key components of the spliceosome. Group II introns are found in all three domains of life and are therefore considered to be exceptionally successful mobile genetic elements. Initially identified in organellar genomes, group II introns are found in bacteria, chloroplasts, and mitochondria of plants and fungi, but not in nuclear genomes. Although there is no doubt that prokaryotic and organellar group II introns are evolutionary related, there are remarkable differences in survival strategies between them. Furthermore, an evolutionary relationship of group II introns to eukaryotic retroelements, including telomeres, and spliceosomes is unmistakable.

  • Aneuploidy Police Detect Chromosomal Imbalance Triggering Immune Crackdown!
    Trends Genet. (IF 10.844) Pub Date : 2017-08-08
    Emma V. Watson, Stephen J. Elledge

    Aneuploidy is ubiquitous in cancer and plays a pivotal, early role in tumor evolution. It must therefore be avoided, and two recent papers highlight the roles of p53, senescence, and the immune system in preventing the outgrowth of aneuploid clones in tissue culture. These mechanisms are likely to synergize to maintain diploid cell populations.

  • Transposable Elements Direct The Coevolution between Plants and Microbes
    Trends Genet. (IF 10.844) Pub Date : 2017-08-08
    Michael F. Seidl, Bart P.H.J. Thomma

    Transposable elements are powerful drivers of genome evolution in many eukaryotes. Although they are mostly considered as ‘selfish’ genetic elements, increasing evidence suggests that they contribute to genetic variability; particularly under stress conditions. Over the past few years, the role of transposable elements during host–microbe interactions has been recognised. It has been proposed that many pathogenic microbes have evolved a ‘two-speed’ genome with regions that show increased variability and that are enriched in transposable elements and pathogenicity-related genes. Plants similarly display structured genomes with transposable-element-rich regions that mediate accelerated evolution. Immune receptor genes typically reside in such regions. Various mechanisms have recently been identified through which transposable elements contribute to the coevolution between plants and their associated microbes.

  • L1 Mosaicism in Mammals: Extent, Effects, and Evolution
    Trends Genet. (IF 10.844) Pub Date : 2017-08-07
    Geoffrey J. Faulkner, Jose L. Garcia-Perez

    The retrotransposon LINE-1 (long interspersed element 1, L1) is a transposable element that has extensively colonized the mammalian germline. L1 retrotransposition can also occur in somatic cells, causing genomic mosaicism, as well as in cancer. However, the extent of L1-driven mosaicism arising during ontogenesis is unclear. We discuss here recent experimental data which, at a minimum, fully substantiate L1 mosaicism in early embryonic development and neural cells, including post-mitotic neurons. We also consider the possible biological impact of somatic L1 insertions in neurons, the existence of donor L1s that are highly active (‘hot’) in specific spatiotemporal niches, and the evolutionary selection of donor L1s driving neuronal mosaicism.

  • Driving to Cancer on a Four-Lane Expressway
    Trends Genet. (IF 10.844) Pub Date : 2017-06-28
    Lorenzo Galluzzi, Ilio Vitale

    Recent findings from a prospective clinical study involving multiregion whole-exome sequencing suggest that driver mutations in cancer-relevant genes including EGFR and TP53 are often clonal and precede whole-genome duplication events in early lung carcinogenesis. This paves an expressway to extensive subclonal diversification, elevated intratumoral heterogeneity, and dismal disease outcome.

  • The Genes That Make a Good Parent
    Trends Genet. (IF 10.844) Pub Date : 2017-06-17
    Reinmar Hager

    What is the genetic basis of differences in parental care between promiscuous and monogamous mammal species? A team led by Hopi Hoekstra studied an intercross between deer mice and old-field mice that differ in their mating systems and parental behaviours. The authors discovered 12 genomic regions contributing to those differences and identified vasopressin as a regulator of nestbuilding behaviour.

  • Genome-wide Mapping of the Nucleosome Landscape by Micrococcal Nuclease and Chemical Mapping
    Trends Genet. (IF 10.844) Pub Date : 2017-07-07
    Lilien N. Voong, Liqun Xi, Ji-Ping Wang, Xiaozhong Wang

    Nucleosomes regulate the transcription output of the genome by occluding the underlying DNA sequences from DNA-binding proteins that must act on it. Knowledge of the precise locations of nucleosomes in the genome is thus essential towards understanding how transcription is regulated. Current nucleosome-mapping strategies involve digesting chromatin with nucleases or chemical cleavage followed by high-throughput sequencing. In this review, we compare the traditional micrococcal nuclease (MNase)-based approach with a chemical cleavage strategy, with discussion on the important insights each has uncovered about the role of nucleosomes in shaping transcriptional processes.

  • Mining Metagenomic Data Sets for Ancient DNA: Recommended Protocols for Authentication
    Trends Genet. (IF 10.844) Pub Date : 2017-07-05
    Felix M. Key, Cosimo Posth, Johannes Krause, Alexander Herbig, Kirsten I. Bos

    While a comparatively young area of research, investigations relying on ancient DNA data have been highly valuable in revealing snapshots of genetic variation in both the recent and the not-so-recent past. Born out of a tradition of single-locus PCR-based approaches that often target individual species, stringent criteria for both data acquisition and analysis were introduced early to establish high standards of data quality. Today, the immense volume of data made available through next-generation sequencing has significantly increased the analytical resolution offered by processing ancient tissues and permits parallel analyses of host and microbial communities. The adoption of this new approach to data acquisition, however, requires an accompanying update on methods of DNA authentication, especially given that ancient molecules are expected to exist in low proportions in archaeological material, where an environmental signal is likely to dominate. In this review, we provide a summary of recent data authentication approaches that have been successfully used to distinguish between endogenous and nonendogenous DNA sequences in metagenomic data sets. While our discussion mostly centers on the detection of ancient human and ancient bacterial pathogen DNA, their applicability is far wider.

  • Antibiotic-Independent Adaptive Effects of Antibiotic Resistance Mutations
    Trends Genet. (IF 10.844) Pub Date : 2017-06-16
    Ruth Hershberg

    Antibiotic usage selects for the accumulation and spread of antibiotic-resistant bacteria. However, resistance can also accumulate in the absence of antibiotic exposure. Antibiotics are often designed to target widely distributed regulatory housekeeping genes. The targeting of such genes enables these antibiotics to be useful against a wider variety of pathogens. This review highlights work suggesting that regulatory housekeeping genes of the type targeted by many antibiotics function as hubs of adaptation to conditions unrelated to antibiotic exposure. As a result of this, some mutations to the regulatory housekeeping gene targets of antibiotics confer both antibiotic resistance and an adaptive effect unrelated to antibiotic exposure. Such antibiotic-independent adaptive effects of resistance mutations may substantially affect the dynamics of antibiotic resistance accumulation and spread.

  • Uncovering Gene Regulatory Networks Controlling Plant Cell Differentiation
    Trends Genet. (IF 10.844) Pub Date : 2017-06-21
    Colleen Drapek, Erin E. Sparks, Philip N. Benfey

    The development of multicellular organisms relies on the precise regulation of cellular differentiation. As such, there has been significant effort invested to understand the process through which an immature cell undergoes differentiation. In this review, we highlight key discoveries and advances that have contributed to our understanding of the transcriptional networks underlying Arabidopsis root endodermal differentiation. To conclude, we propose perspectives on how advances in molecular biology, microscopy, and nucleotide sequencing will provide the tools to test the biological significance of these gene regulatory networks (GRN).

  • The Diversity of Long Noncoding RNAs and Their Generation
    Trends Genet. (IF 10.844) Pub Date : 2017-06-16
    Huang Wu, Li Yang, Ling-Ling Chen

    Long noncoding RNAs (lncRNAs) are emerging as potential key regulators in gene expression networks and exhibit a surprising range of shapes and sizes. Several distinct classes of lncRNAs are transcribed from different DNA elements, including promoters, enhancers, and intergenic regions in eukaryotic genomes. Additionally, others are derived from long primary transcripts with noncanonical RNA processing pathways, generating new RNA species with unexpected formats. These lncRNAs can be processed by several mechanisms, including ribonuclease P (RNase P) cleavage to generate mature 3′ ends, capping by small nucleolar RNA (snoRNA)–protein (snoRNP) complexes at their ends, or the formation of circular structures. Here we review current knowledge on lncRNAs and highlight the most recent discoveries of the underlying mechanisms related to their formation.

  • Advances in Decoding Axolotl Limb Regeneration
    Trends Genet. (IF 10.844) Pub Date : 2017-06-22
    Brian J. Haas, Jessica L. Whited

    Humans and other mammals are limited in their natural abilities to regenerate lost body parts. By contrast, many salamanders are highly regenerative and can spontaneously replace lost limbs even as adults. Because salamander limbs are anatomically similar to human limbs, knowing how they regenerate should provide important clues for regenerative medicine. Although interest in understanding the mechanics of this process has never wavered, until recently researchers have been vexed by seemingly impenetrable logistics of working with these creatures at a molecular level. Chief among the problems has been the very large size of salamander genomes, and not a single salamander genome has been fully sequenced to date. Recently the enormous gap in sequence information has been bridged by approaches that leverage mRNA as the starting point. Together with functional experimentation, these data are rapidly enabling researchers to finally uncover the molecular mechanisms underpinning the astonishing biological process of limb regeneration.

  • Histone H2A Monoubiquitination in Neurodevelopmental Disorders
    Trends Genet. (IF 10.844) Pub Date : 2017-06-29
    Anshika Srivastava, Brian McGrath, Stephanie L. Bielas

    Covalent histone modifications play an essential role in gene regulation and cellular specification required for multicellular organism development. Monoubiquitination of histone H2A (H2AUb1) is a reversible transcriptionally repressive mark. Exchange of histone H2A monoubiquitination and deubiquitination reflects the succession of transcriptional profiles during development required to produce cellular diversity from pluripotent cells. Germ-line pathogenic variants in components of the H2AUb1 regulatory axis are being identified as the genetic basis of congenital neurodevelopmental disorders. Here, we review the human genetics findings coalescing on molecular mechanisms that alter the genome-wide distribution of this histone modification required for development.

  • On the Origin of lncRNAs: Missing Link Found
    Trends Genet. (IF 10.844) Pub Date : 2017-08-01
    Joaquín M. Espinosa

    Non-coding (nc)RNAs known as enhancer-derived RNAs (eRNAs) and as long ncRNAs (lncRNAs) have received much attention, but their true functional specialization and evolutionary origins remain obscure. The recent characterization of Bloodlinc, an eRNA derived from a super-enhancer that also functions as a lncRNA, suggests that lncRNAs can evolve from eRNAs.

  • A Fundamental Unit of Cell Size in Bacteria
    Trends Genet. (IF 10.844) Pub Date : 2017-05-22
    Suckjoon Jun, Michael J. Rust

    A new study clarifies a relationship between growth, gene expression, and cell size in cyanobacteria. Quite unexpectedly, cyanobacteria and Escherichia coli appear to share an invariance principle to coordinate growth and chromosome replication. This principle allows quantitative predictions of cell size across a range of growth conditions in both organisms.

  • Perspectives on Gene Regulatory Network Evolution
    Trends Genet. (IF 10.844) Pub Date : 2017-05-18
    Marc S. Halfon

    Animal development proceeds through the activity of genes and their cis-regulatory modules (CRMs) working together in sets of gene regulatory networks (GRNs). The emergence of species-specific traits and novel structures results from evolutionary changes in GRNs. Recent work in a wide variety of animal models, and particularly in insects, has started to reveal the modes and mechanisms of GRN evolution. I discuss here various aspects of GRN evolution and argue that developmental system drift (DSD), in which conserved phenotype is nevertheless a result of changed genetic interactions, should regularly be viewed from the perspective of GRN evolution. Advances in methods to discover related CRMs in diverse insect species, a critical requirement for detailed GRN characterization, are also described.

  • Mosaicism in Preimplantation Human Embryos: When Chromosomal Abnormalities Are the Norm
    Trends Genet. (IF 10.844) Pub Date : 2017-04-28
    Rajiv C. McCoy

    Along with errors in meiosis, mitotic errors during post-zygotic cell division contribute to pervasive aneuploidy in human embryos. Relatively little is known, however, about the genesis of these errors or their fitness consequences. Rapid technological advances are helping to close this gap, revealing diverse molecular mechanisms contributing to mitotic error. These include altered cell cycle checkpoints, aberrations of the centrosome, and failed chromatid cohesion, mirroring findings from cancer biology. Recent studies are challenging the idea that mitotic error is abnormal, emphasizing that the fitness impacts of mosaicism depend on its scope and severity. In light of these findings, technical and philosophical limitations of various screening approaches are discussed, along with avenues for future research.

  • The Dimensions, Dynamics, and Relevance of the Mammalian Noncoding Transcriptome
    Trends Genet. (IF 10.844) Pub Date : 2017-05-20
    Ira W. Deveson, Simon A. Hardwick, Tim R. Mercer, John S. Mattick

    The combination of pervasive transcription and prolific alternative splicing produces a mammalian transcriptome of great breadth and diversity. The majority of transcribed genomic bases are intronic, antisense, or intergenic to protein-coding genes, yielding a plethora of short and long non-protein-coding regulatory RNAs. Long noncoding RNAs (lncRNAs) share most aspects of their biogenesis, processing, and regulation with mRNAs. However, lncRNAs are typically expressed in more restricted patterns, frequently from enhancers, and exhibit almost universal alternative splicing. These features are consistent with their role as modular epigenetic regulators. We describe here the key studies and technological advances that have shaped our understanding of the dimensions, dynamics, and biological relevance of the mammalian noncoding transcriptome.

  • V(D)J Recombination Exploits DNA Damage Responses to Promote Immunity
    Trends Genet. (IF 10.844) Pub Date : 2017-05-19
    Rahul Arya, Craig H. Bassing

    It has been recognized for 40 years that the variable (diversity) joining [V(D)J] recombination-mediated assembly of diverse B and T lymphocyte antigen receptor (AgR) genes is not only essential for adaptive immunity, but also a risk for autoimmunity and lymphoid malignancies. Over the past few years, several studies have revealed that recombination-activating gene (RAG) endonuclease-induced DNA double-strand breaks (DSBs) transcend hazardous intermediates during antigen receptor gene assembly. RAG cleavage within the genomes of lymphocyte progenitors and immature lymphocytes regulates the expression of ubiquitous and lymphocyte-specific gene transcripts to control the differentiation and function of both adaptive and innate immune cell lineages. These unexpected discoveries raise important new questions that have broad implications for basic immunology research and the screening, diagnosis, and treatment of human immunological disease.

  • Enhancer-Derived lncRNAs Regulate Genome Architecture: Fact or Fiction?
    Trends Genet. (IF 10.844) Pub Date : 2017-03-27
    Stephanie Fanucchi, Musa M. Mhlanga

    How does the non-coding portion of the genome contribute to the regulation of genome architecture? A recent paper by Tan et al. focuses on the relationship between cis-acting complex-trait-associated lincRNAs and the formation of chromosomal contacts in topologically associating domains (TADs).

  • Gene Duplicates: Agents of Robustness or Fragility?
    Trends Genet. (IF 10.844) Pub Date : 2017-04-20
    Reiner A. Veitia

    A recent analysis of paralog deletion in yeast has shown that functional compensation and dependency occur equally. While theory predicts that compensation produces robustness, the authors hypothesized that stabilization of one paralogous protein through interaction with its copy could explain dependency. Here, we provide alternative explanations, such as selection for increased protein dosage and hypofunctionalization.

  • m6A in mRNA: An Ancient Mechanism for Fine-Tuning Gene Expression
    Trends Genet. (IF 10.844) Pub Date : 2017-05-09
    Jean-Yves Roignant, Matthias Soller

    Modifications in mRNA constitute ancient mechanisms to regulate gene expression post-transcriptionally. N6-methyladenosine (m6A) is the most prominent mRNA modification, and is installed by a large methyltransferase complex (the m6A ‘writer’), not only specifically bound by RNA-binding proteins (the m6A ‘readers’), but also removed by demethylases (the m6A ‘erasers’). m6A mRNA modifications have been linked to regulation at multiple steps in mRNA processing. In analogy to the regulation of gene expression by miRNAs, we propose that the main function of m6A is post-transcriptional fine-tuning of gene expression. In contrast to miRNA regulation, which mostly reduces gene expression, we argue that m6A provides a fast mean to post-transcriptionally maximize gene expression. Additionally, m6A appears to have a second function during developmental transitions by targeting m6A-marked transcripts for degradation.

  • Etiology of Human Genetic Disease on the Fly
    Trends Genet. (IF 10.844) Pub Date : 2017-04-15
    Clement Y. Chow, Lawrence T. Reiter

    The model organism Drosophila melanogaster has been at the forefront of genetic studies since before the discovery of DNA. Although human disease modeling in flies may still be rather novel, recent advances in genetic tool design and genome sequencing now confer huge advantages in the fly system when modeling human disease. In this review, we focus on new genomic tools for human gene variant analysis; new uses for the Drosophila Genetic Reference Panel (DGRP) in detection of background alleles that influence a phenotype; and several examples of how multigenic conditions, both complex disorders and duplication and/or deletion syndromes, can be effectively studied in the fly model system. Fruit flies are a far cry from the quaint genetic model of the past, but rather, continue to evolve as a powerful system for the study of human genetic disease.

  • Developmental and Transmittable Origins of Obesity-Associated Health Disorders
    Trends Genet. (IF 10.844) Pub Date : 2017-04-21
    Arin K. Oestreich, Kelle H. Moley

    The current global obesity pandemic is clearly linked to both the increasing prevalence of, and preference for, foods high in calories, specifically fat and sucrose, and declining levels of daily physical activity. A less commonly discussed possible explanation is that risk of obesity begins in utero as a result of developmental plasticity during early life. This idea fits into the broader Developmental Origins of Health and Diseases (DOHAD) hypothesis, which holds that stressful in utero exposure manifests as disease in adulthood. In this review, we highlight several studies that have revealed the role of epigenetics in multigenerational transmission of developmentally programmed obesity and associated cardiometabolic disease.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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