Biology subjects

Friedrich, M.

Publications and source records attributed to Friedrich, M..

27 records · Page 2Linked to original sources

bioRxiv2020

Centrosome impairment causes DNA replication stress through MLK3/MK2 signaling and R-loop formation

AO_SCPLOWBSTRACTC_SCPLOWCentrosomes function as organizing centers of microtubules and support accurate mitosis in many animal cells. However, it remains to be explored whether and how centrosomes also facilitate the progression through different phases of the cell cycle. Here we show that impairing the composition of centrosomes, by depletion of centrosomal components or by inhibition of polo-like kinase 4 (PLK4), reduces the progression of DNA replication forks. This occurs even when the cell cycle is arrested before damaging the centrosomes, thus excluding mitotic failure as the source of replication stress. Mechanistically, the kinase MLK3 associates with centrosomes. When centrosomes are disintegrated, MLK3 activates the kinases p38 and MK2/MAPKAPK2. Transcription-dependent RNA:DNA hybrids (R-loops) are then causing DNA replication stress. Fibroblasts from patients with microcephalic primordial dwarfism (Seckel syndrome) harbouring defective centrosomes showed replication stress and diminished proliferation, which were each alleviated by inhibition of MK2. Thus, centrosomes not only facilitate mitosis, but their integrity is also supportive in DNA replication. HighlightsO_LICentrosome defects cause replication stress independent of mitosis. C_LIO_LIMLK3, p38 and MK2 (alias MAPKAPK2) are signalling between centrosome defects and DNA replication stress through R-loop formation. C_LIO_LIPatient-derived cells with defective centrosomes display replication stress, whereas inhibition of MK2 restores their DNA replication fork progression and proliferation. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/898684v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@41a10corg.highwire.dtl.DTLVardef@b4328dorg.highwire.dtl.DTLVardef@62f373org.highwire.dtl.DTLVardef@5d2c40_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

Functional genomics of the stable fly, Stomoxys calcitrans, reveals mechanisms underlying reproduction, host interactions, and novel targets for pest control

BackgroundThe stable fly, Stomoxys calcitrans, is a major blood-feeding pest of livestock that has near worldwide distribution, causing an annual cost of over $2 billion for control and product loss in the United States alone. Control of these flies has been limited to increased sanitary management practices and insecticide application for suppressing larval stages. Few genetic and molecular resources are available to help in developing novel methods for controlling stable flies.\n\nResultsThis study examines stable fly biology by utilizing a combination of high-quality genome sequencing, microbiome analyses, and RNA-seq analyses targeting multiple developmental stages and tissues. In conjunction, manual curation of over 1600 genes was used to examine gene content related to stable fly reproduction, interactions with their host, host-microbe dynamics, and putative routes for control. Most notable was establishment of reproduction-associated genes and identification of expanded vision, chemosensation, immune repertoire, and metabolic detoxification pathway gene families.\n\nConclusionsThe combined sequencing, assembly, and curation of the male stable fly genome followed by RNA-seq and downstream analyses provide insights necessary to understand the biology of this important pest. These resources and knowledge will provide the groundwork for expanding the tools available to control stable fly infestations. The close relationship of Stomoxys to other blood-feeding (Glossina) and non-blood-feeding flies (medflies, Drosophila, house flies) will allow for understanding the evolution of blood feeding among Cyclorrhapha flies.

genomics↗

bioRxiv2019

CD2 expression acts as a quantitative checkpoint for immunological synapse structure and T-cell activation.

The CD2 receptor has been described as an adhesion and costimulatory receptor on T cells. Here, transcriptional profiling of colorectal cancers (CRC) revealed a negative correlation between CD2 expression and \"exhausted CD8+ T-cells\" gene signatures. Furthermore, we detected reduced surface CD2 levels in exhausted CD127lowPD-1hi CD3+CD8+ tumour infiltrating lymphocytes (TILs) in CRC. We describe a CD2 expression-level-dependent switch in CD2-CD58 localization between central and peripheral domains in the immunological synapse (IS). A peripheral \"CD2 corolla\" formed when CD2 surface expression was sufficiently high and its cytoplasmic domain intact. The corolla recruited other ligated receptors like CD28, boosted recruitment of activated Src-family kinases (pSrc), LAT and PLC-{gamma} in the IS and consequently T-cell activation in response to a tumour antigen. Corolla formation and pSrc in the IS increased linearly with CD2 expression, whereas pSrc signals were reduced by high, \"exhausted-like\" levels of PD-1, which invaded the corolla. These results suggest two levels of inhibition of Src-family kinases in CD3+CD8+ TILs: reduced CD2 expression and high PD-1 expression.

immunology↗

bioRxiv2019

The Glossina Genome Cluster: Comparative Genomic Analysis of the Vectors of African Trypanosomes

BackgroundTsetse flies (Glossina sp.) are the sole vectors of human and animal trypanosomiasis throughout sub-Saharan Africa. Tsetse are distinguished from other Diptera by unique adaptations, including lactation and the birthing of live young (obligate viviparity), a vertebrate blood specific diet by both sexes and obligate bacterial symbiosis. This work describes comparative analysis of six Glossina genomes representing three sub-genera: Morsitans (G. morsitans morsitans (G.m. morsitans), G. pallidipes, G. austeni), Palpalis (G. palpalis, G. fuscipes) and Fusca (G. brevipalpis) which represent different habitats, host preferences and vectorial capacity. ResultsGenomic analyses validate established evolutionary relationships and sub-genera. Syntenic analysis of Glossina relative to Drosophila melanogaster shows reduced structural conservation across the sex-linked X chromosome. Sex linked scaffolds show increased rates of female specific gene expression and lower evolutionary rates relative to autosome associated genes. Tsetse specific genes are enriched in protease, odorant binding and helicase activities. Lactation associated genes are conserved across all Glossina species while male seminal proteins are rapidly evolving. Olfactory and gustatory genes are reduced across the genus relative to other characterized insects. Vision associated Rhodopsin genes show conservation of motion detection/tracking functions and significant variance in the Rhodopsin detecting colors in the blue wavelength ranges. ConclusionsExpanded genomic discoveries reveal the genetics underlying Glossina biology and provide a rich body of knowledge for basic science and disease control. They also provide insight into the evolutionary biology underlying novel adaptations and are relevant to applied aspects of vector control such as trap design and discovery of novel pest and disease control strategies.

genomics↗

bioRxiv2018

TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions

MAIT cells are an abundant T cell population that are highly enriched in epithelial tissues such as the liver. They are known to be activated both through TCR-dependent and -independent mechanisms. However, the specific functional responses of MAIT cells to these signals remain elusive. We examined the impact of combinations of TCR-dependent and -independent signals in blood and tissue-derived human MAIT cells. TCR-dependent and -independent signals drive MAIT cells to exert overlapping and unique effector functions. Importantly, this includes several novel functions that are relevant not only to host defence but also tissue homeostasis. While TCR triggering is insufficient to drive sustained activation, gene expression signatures of TCR-triggered MAIT cells also showed specific enrichment of tissue-repair functions. Activation of certain effector and antimicrobial functions may be triggered further with specific innate cytokine signals, such as the TNF superfamily member TL1A. In addition, gut-resident cells exposed to commensal-derived ligands showed evidence of persistent activation in vivo. Taken together, this study demonstrates the pivotal role of MAIT cells in controlling the balance between healthy and pathological processes of tissue inflammation and repair.

immunology↗

bioRxiv2018

The Genomic Basis of Arthropod Diversity

BackgroundArthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods.\n\nResultsUsing 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality and chemoperception.\n\nConclusionsThese analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity.

genomics↗

bioRxiv2018

The genome of the water strider Gerris buenoi reveals expansions of gene repertoires associated with adaptations to life on the water

The semi-aquatic bugs conquered water surfaces worldwide and occupy ponds, streams, lakes, mangroves, and even open oceans. As such, they inspired a range of scientific studies from ecology and evolution to developmental genetics and hydrodynamics of fluid locomotion. However, the lack of a representative water strider genome hinders thorough investigations of the mechanisms underlying the processes of adaptation and diversification in this group. Here we report the sequencing and manual annotation of the Gerris buenoi (G. buenoi) genome, the first water strider genome to be sequenced so far. G. buenoi genome is about 1 000Mb and the sequencing effort recovered 20 949 predicted protein-coding genes. Manual annotation uncovered a number of local (tandem and proximal) gene duplications and expansions of gene families known for their importance in a variety of processes associated with morphological and physiological adaptations to water surface lifestyle. These expansions affect key processes such as growth, vision, desiccation resistance, detoxification, olfaction and epigenetic components. Strikingly, the G. buenoi genome contains three Insulin Receptors, a unique case among metazoans, suggesting key changes in the rewiring and function of the insulin pathway. Other genomic changes include wavelength sensitivity shifts in opsin proteins likely in association with the requirements of vision in water habitats. Our findings suggest that local gene duplications might have had an important role during the evolution of water striders. These findings along with the G. buenoi genome open exciting research opportunities to understand adaptation and genome evolution of this unique hemimetabolous insect.

genomics↗

bioRxiv2017

Molecular evolutionary trends and feeding ecology diversification in the Hemiptera, anchored by the milkweed bug genome

BackgroundThe Hemiptera (aphids, cicadas, and true bugs) are a key insect order, with high diversity for feeding ecology and excellent experimental tractability for molecular genetics. Building upon recent sequencing of hemipteran pests such as phloem-feeding aphids and blood-feeding bed bugs, we present the genome sequence and comparative analyses centered on the milkweed bug Oncopeltus fasciatus, a seed feeder of the family Lygaeidae.\n\nResultsThe 926-Mb Oncopeltus genome is well represented by the current assembly and official gene set. We use our genomic and RNA-seq data not only to characterize the protein-coding gene repertoire and perform isoform-specific RNAi, but also to elucidate patterns of molecular evolution and physiology. We find ongoing, lineage-specific expansion and diversification of repressive C2H2 zinc finger proteins. The discovery of intron gain and turnover specific to the Hemiptera also prompted evaluation of lineage and genome size as predictors of gene structure evolution. Furthermore, we identify enzymatic gains and losses that correlate with feeding biology, particularly for reductions associated with derived, fluid-nutrition feeding.\n\nConclusionsWith the milkweed bug, we now have a critical mass of sequenced species for a hemimetabolous insect order and close outgroup to the Holometabola, substantially improving the diversity of insect genomics. We thereby define commonalities among the Hemiptera and delve into how hemipteran genomes reflect distinct feeding ecologies. Given Oncopeltus's strength as an experimental model, these new sequence resources bolster the foundation for molecular research and highlight technical considerations for the analysis of medium-sized invertebrate genomes.

genomics↗

bioRxiv2017

A model species for agricultural pest genomics: the genome of the Colorado potato beetle, Leptinotarsa decemlineata (Coleoptera: Chrysomelidae)

The Colorado potato beetle is one of the most challenging agricultural pests to manage. It has shown a spectacular ability to adapt to a variety of solanaceaeous plants and variable climates during its global invasion, and, notably, to rapidly evolve insecticide resistance. To examine evidence of rapid evolutionary change, and to understand the genetic basis of herbivory and insecticide resistance, we tested for structural and functional genomic changes relative to other arthropod species using genome sequencing, transcriptomics, and community annotation. Two factors that might facilitate rapid evolutionary change include transposable elements, which comprise at least 17% of the genome and are rapidly evolving compared to other Coleoptera, and high levels of nucleotide diversity in rapidly growing pest populations. Adaptations to plant feeding are evident in gene expansions and differential expression of digestive enzymes in gut tissues, as well as expansions of gustatory receptors for bitter tasting. Surprisingly, the suite of genes involved in insecticide resistance is similar to other beetles. Finally, duplications in the RNAi pathway might explain why Leptinotarsa decemlineata has high sensitivity to dsRNA. The L. decemlineata genome provides opportunities to investigate a broad range of phenotypes and to develop sustainable methods to control this widely successful pest.

genomics↗