Publications

The Babraham Institute Publications database contains details of all publications resulting from our research groups and scientific services.

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Title / Authors / Details Open Access Download

Age-related changes in the physical properties, cross-linking, and glycation of collagen from mouse tail tendon.
Stammers M, Ivanova IM, Niewczas IS, Segonds-Pichon A, Streeter M, Spiegel DA, Clark J

Collagen is a structural protein whose internal cross-linking critically determines the properties and functions of connective tissue. Knowing how the cross-linking of collagen changes with age is key to understanding why the mechanical properties of tissues change over a lifetime. The current scientific consensus is that collagen cross-linking increases with age and that this increase leads to tendon stiffening. Here, we show that this view should be reconsidered. Using MS-based analyses, we demonstrate that during aging of healthy C57BL/6 mice, the overall levels of collagen cross-linking in tail tendon decrease with age. However, the levels of lysine glycation in collagen, which is not considered a cross-link, increased dramatically with age. We found that in 16-week-old diabetic db/db mice, glycation reaches levels similar to those observed in 98-week-old C57BL/6 mice, while the other cross-links typical of tendon collagen either decreased or remained the same as those observed in 20 week old WT mice. These results, combined with findings from mechanical testing of tendons from these mice, indicate that overall collagen cross-linking in mouse tendon decreases with age. Our findings also reveal that lysine glycation appears to be an important factor that contributes to tendon stiffening with age and in diabetes.

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The Journal of biological chemistry , 1 , 1 ,

PMID: 32381510

Open Access

Leptin Resistance in the Ovary of Obese Mice is Associated with Profound Changes in the Transcriptome of Cumulus Cells.
Wołodko K, Walewska E, Adamowski M, Castillo-Fernandez J, Kelsey G, Galvão A

Obesity is associated with infertility, decreased ovarian performance and lipotoxicity. However, little is known about the aetiology of these reproductive impairments. Here, we hypothesise that the majority of changes in ovarian physiology in diet-induced obesity (DIO) are a consequence of transcriptional changes downstream of altered leptin signalling. Therefore, we investigated the extent to which leptin signalling is altered in the ovary upon obesity with particular emphasis on effects on cumulus cells (CCs), the intimate functional companions of the oocyte. Furthermore, we used the pharmacological hyperleptinemic (LEPT) mouse model to compare transcriptional profiles to DIO.

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Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology , 54 , 3 ,

PMID: 32348667

Open Access

Bile acids mediate signaling between microbiome and the immune system.
Liston A, Whyte CE

The microbiome is increasingly recognized for its ability to modulate human health. Colonization with gut symbionts induces Foxp3‐expressing regulatory T cells (Tregs) and expands their local numbers, a critical step in the suppression of intestinal inflammation and maintaining gut homeostasis. The molecular mechanism by which the microbiome interacts with peripherally induced Treg (pTreg) is likely complex and multifactorial; however, part of the effect is mediated via the release of microbial fermentation products, such as butyrate and other short‐chain fatty acids.

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Immunology and cell biology , 1 , 1 ,

PMID: 32329090

Stromal cell control of conventional and ectopic germinal centre reactions.
Silva-Cayetano A, Linterman MA

The germinal centre (GC) is a specialized cellular structure that forms in response to antigenic stimulation. It generates long-term humoral immunity through the production of memory B cells and long-lived antibody-secreting plasma cells. Conventional GCs form within secondary lymphoid organs, where networks of specialised stromal cells that form during embryogenesis act as the stage upon which the various GC immune cell players are brought together, nurtured and co-ordinated to generate a productive response. In non-lymphoid organs, ectopic GCs can form in response to persistent antigenic and inflammatory stimuli. Unlike secondary lymphoid tissues, non-lymphoid organs do not have a developmentally programmed stromal cell network capable of supporting the germinal centre reaction; therefore, the local tissue stroma must be remodelled by inflammatory stimuli in order to host a GC reaction. These ectopic GCs produce memory B cells and plasma cells that form a critical component of the humoral immune response.

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Current opinion in immunology , 64 , 1 ,

PMID: 32325390

Defective SEC61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
Van Nieuwenhove E, Barber JS, Neumann J, Smeets E, Willemsen M, Pasciuto E, Prezzemolo T, Lagou V, Seldeslachts L, Malengier-Devlies B, Metzemaekers M, Haßdenteufel S, Kerstens A, van der Kant R, Rousseau F, Schymkowitz J, Di Marino D, Lang S, Zimmermann R, Schlenner S, Munck S, Proost P, Matthys P, Devalck C, Boeckx N, Claessens F, Wouters C, Humblet-Baron S, Meyts I, Liston A

The molecular cause of severe congenital neutropenia (SCN) is unknown in 30-50% of patients. SEC61A1 encodes the α subunit of the SEC61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease.

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The Journal of allergy and clinical immunology , 1 , 1 ,

PMID: 32325141

Placental imprinting: Emerging mechanisms and functions.
Hanna CW

As the maternal-foetal interface, the placenta is essential for the establishment and progression of healthy pregnancy, regulating both foetal growth and maternal adaptation to pregnancy. The evolution and functional importance of genomic imprinting are inextricably linked to mammalian placentation. Recent technological advances in mapping and manipulating the epigenome in embryogenesis in mouse models have revealed novel mechanisms regulating genomic imprinting in placental trophoblast, the physiological implications of which are only just beginning to be explored. This review will highlight important recent discoveries and exciting new directions in the study of placental imprinting.

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PLoS genetics , 16 , 4 ,

PMID: 32324732

Open Access

ATG13 dynamics in nonselective autophagy and mitophagy: insights from live imaging studies and mathematical modeling.
Dalle Pezze P, Karanasios E, Kandia V, Manifava M, Walker SA, Gambardella Le Novère N, Ktistakis NT

During macroautophagy/autophagy, the ULK complex nucleates autophagic precursors, which give rise to autophagosomes. We analyzed, by live imaging and mathematical modeling, the translocation of ATG13 (part of the ULK complex) to the autophagic puncta in starvation-induced autophagy and ivermectin-induced mitophagy. In nonselective autophagy, the intensity and duration of ATG13 translocation approximated a normal distribution, whereas wortmannin reduced this effect and shifted to a log-normal distribution. During mitophagy, multiple translocations of ATG13 with increasing time between peaks were observed. We hypothesized that these multiple translocations arise because the engulfment of mitochondrial fragments required successive nucleation of phagophores on the same target, and a mathematical model based on this idea reproduced the oscillatory behavior. Significantly, model and experimental data were also in agreement that the number of ATG13 translocations is directly proportional to the diameter of the targeted mitochondrial fragments. Thus, our data provide novel insights into the early dynamics of selective and nonselective autophagy. ATG: autophagy related 13; CFP: cyan fluorescent protein; dsRED: red fluorescent protein; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; IVM: ivermectin; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3P: PtdIns-3-phosphate; ULK: unc-51 like autophagy activating kinase.

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Autophagy , 1 , 1 ,

PMID: 32320309

Cell-Surface Proteomics Identifies Differences in Signaling and Adhesion Protein Expression between Naive and Primed Human Pluripotent Stem Cells.
Wojdyla K, Collier AJ, Fabian C, Nisi PS, Biggins L, Oxley D, Rugg-Gunn PJ

Naive and primed human pluripotent stem cells (hPSC) provide valuable models to study cellular and molecular developmental processes. The lack of detailed information about cell-surface protein expression in these two pluripotent cell types prevents an understanding of how the cells communicate and interact with their microenvironments. Here, we used plasma membrane profiling to directly measure cell-surface protein expression in naive and primed hPSC. This unbiased approach quantified over 1,700 plasma membrane proteins, including those involved in cell adhesion, signaling, and cell interactions. Notably, multiple cytokine receptors upstream of JAK-STAT signaling were more abundant in naive hPSC. In addition, functional experiments showed that FOLR1 and SUSD2 proteins are highly expressed at the cell surface in naive hPSC but are not required to establish human naive pluripotency. This study provides a comprehensive stem cell proteomic resource that uncovers differences in signaling pathway activity and has identified new markers to define human pluripotent states.

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Stem cell reports , 1 , 1 ,

PMID: 32302559

Open Access

The adaptive potential of circular DNA accumulation in ageing cells.
Hull RM, Houseley J

Carefully maintained and precisely inherited chromosomal DNA provides long-term genetic stability, but eukaryotic cells facing environmental challenges can benefit from the accumulation of less stable DNA species. Circular DNA molecules lacking centromeres segregate randomly or asymmetrically during cell division, following non-Mendelian inheritance patterns that result in high copy number instability and massive heterogeneity across populations. Such circular DNA species, variously known as extrachromosomal circular DNA (eccDNA), microDNA, double minutes or extrachromosomal DNA (ecDNA), are becoming recognised as a major source of the genetic variation exploited by cancer cells and pathogenic eukaryotes to acquire drug resistance. In budding yeast, circular DNA molecules derived from the ribosomal DNA (ERCs) have been long known to accumulate with age, but it is now clear that aged yeast also accumulate other high-copy protein-coding circular DNAs acquired through both random and environmentally-stimulated recombination processes. Here, we argue that accumulation of circular DNA provides a reservoir of heterogeneous genetic material that can allow rapid adaptation of aged cells to environmental insults, but avoids the negative fitness impacts on normal growth of unsolicited gene amplification in the young population.

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Current genetics , 1 , 1 ,

PMID: 32296868

Open Access

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors.
Dembny P, Newman AG, Singh M, Hinz M, Szczepek M, Krüger C, Adalbert R, Dzaye O, Trimbuch T, Wallach T, Kleinau G, Derkow K, Richard BC, Schipke C, Scheidereit C, Stachelscheid H, Golenbock D, Peters O, Coleman M, Heppner FL, Scheerer P, Tarabykin V, Ruprecht K, Izsvák Z, Mayer J, Lehnardt S

Although human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs, such as HERV-K(HML-2), are reported to be involved in neurological disorders, little is known about their biological function. We report that RNA from an HERV-K(HML-2) envelope gene region binds to and activates human Toll-like receptor (TLR) 8, as well as murine Tlr7, expressed in neurons and microglia, thereby causing neurodegeneration. HERV-K(HML-2) RNA introduced into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimer's disease (AD), resulted in neurodegeneration and microglia accumulation. Tlr7-deficient mice were protected against neurodegenerative effects but were resensitized toward HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Transcriptome data sets of human AD brain samples revealed a distinct correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from individuals with AD compared with controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for species-specific TLRs 7/8 and imply a functional contribution of human endogenous retroviral transcripts to neurodegenerative processes, such as AD.

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JCI insight , 5 , 7 ,

PMID: 32271161

Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps.
Zachari M, Ktistakis NT

Mitophagy, a conserved intracellular process by which mitochondria are eliminated via the autophagic machinery, is a quality control mechanism which facilitates maintenance of a functional mitochondrial network and cell homeostasis, making it a key process in development and longevity. Mitophagy has been linked to multiple human disorders, especially neurodegenerative diseases where the long-lived neurons are relying on clearance of old/damaged mitochondria to survive. During the past decade, the availability of novel tools to study mitophagy both and has significantly advanced our understanding of the molecular mechanisms governing this fundamental process in normal physiology and in various disease models. We here give an overview of the known mitophagy pathways and how they are induced, with a particular emphasis on the early events governing mitophagosome formation.

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Frontiers in cell and developmental biology , 8 , 1 ,

PMID: 32258042

Open Access

Low rates of mutation in clinical grade human pluripotent stem cells under different culture conditions.
Thompson O, von Meyenn F, Hewitt Z, Alexander J, Wood A, Weightman R, Gregory S, Krueger F, Andrews S, Barbaric I, Gokhale PJ, Moore HD, Reik W, Milo M, Nik-Zainal S, Yusa K, Andrews PW

The occurrence of repetitive genomic changes that provide a selective growth advantage in pluripotent stem cells is of concern for their clinical application. However, the effect of different culture conditions on the underlying mutation rate is unknown. Here we show that the mutation rate in two human embryonic stem cell lines derived and banked for clinical application is low and not substantially affected by culture with Rho Kinase inhibitor, commonly used in their routine maintenance. However, the mutation rate is reduced by >50% in cells cultured under 5% oxygen, when we also found alterations in imprint methylation and reversible DNA hypomethylation. Mutations are evenly distributed across the chromosomes, except for a slight increase on the X-chromosome, and an elevation in intergenic regions suggesting that chromatin structure may affect mutation rate. Overall the results suggest that pluripotent stem cells are not subject to unusually high rates of genetic or epigenetic alterations.

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Nature communications , 11 , 1 ,

PMID: 32251294

Open Access

Replicative fitness recuperation of a recombinant murine norovirus - reciprocity of genetic shift and drift.
Ludwig-Begall LF, Lu J, Hosmillo M, de Oliveira-Filho EF, Mathijs E, Goodfellow I, Mauroy A, Thiry E

Noroviruses are recognized as the major cause of non-bacterial gastroenteritis in humans. Molecular mechanisms driving norovirus evolution are the accumulation of point mutations and recombination. Recombination can create considerable changes in a viral genome, potentially eliciting a fitness cost, which must be compensated via the adaptive capacity of a recombinant virus. We previously described replicative fitness reduction of the first generated WU20-CW1 recombinant murine norovirus, RecMNV. In this follow-up study, RecMNV's capability of replicative fitness recuperation and genetic characteristics of RecMNV progenies at early and late stages of an adaptation experiment were evaluated. Replicative fitness regain of the recombinant was demonstrated via growth kinetics and plaque size differences between viral progenies prior to and post serial passaging. Point mutations at consensus and sub-consensus population levels of early and late viral progenies were characterized via next-generation sequencing and putatively associated to fitness changes. To investigate the effect of genomic changes separately and in combination in the context of a lab-generated inter-MNV infectious virus, mutations were introduced into a recombinant WU20-CW1 cDNA for subsequent DNA-based reverse genetics recovery. We thus associated fitness loss of RecMNV to a C7245T mutation and functional VP2 (ORF3) truncation and demonstrated individual and cumulative compensatory effects of one synonymous OFR2 and two non-synonymous ORF1 consensus-level mutations acquired during successive rounds of replication. Our data provide evidence of viral adaptation in a controlled environment via genetic drift after genetic shift induced a fitness cost of an infectious recombinant norovirus.

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The Journal of general virology , 1 , 1 ,

PMID: 32242791

Rejuvenating conventional dendritic cells and T follicular helper cell formation after vaccination.
Stebegg M, Bignon A, Hill DL, Silva-Cayetano A, Krueger C, Vanderleyden I, Innocentin S, Boon L, Wang J, Zand MS, Dooley J, Clark J, Liston A, Carr E, Linterman MA

Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.

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eLife , 9 , 1 ,

PMID: 32204792

Open Access

Autophagy compensates for defects in mitochondrial dynamics.
Haeussler S, Köhler F, Witting M, Premm MF, Rolland SG, Fischer C, Chauve L, Casanueva O, Conradt B

Compromising mitochondrial fusion or fission disrupts cellular homeostasis; however, the underlying mechanism(s) are not fully understood. The loss of C. elegans fzo-1MFN results in mitochondrial fragmentation, decreased mitochondrial membrane potential and the induction of the mitochondrial unfolded protein response (UPRmt). We performed a genome-wide RNAi screen for genes that when knocked-down suppress fzo-1MFN(lf)-induced UPRmt. Of the 299 genes identified, 143 encode negative regulators of autophagy, many of which have previously not been implicated in this cellular quality control mechanism. We present evidence that increased autophagic flux suppresses fzo-1MFN(lf)-induced UPRmt by increasing mitochondrial membrane potential rather than restoring mitochondrial morphology. Furthermore, we demonstrate that increased autophagic flux also suppresses UPRmt induction in response to a block in mitochondrial fission, but not in response to the loss of spg-7, which encodes a mitochondrial metalloprotease. Finally, we found that blocking mitochondrial fusion or fission leads to increased levels of certain types of triacylglycerols and that this is at least partially reverted by the induction of autophagy. We propose that the breakdown of these triacylglycerols through autophagy leads to elevated metabolic activity, thereby increasing mitochondrial membrane potential and restoring mitochondrial and cellular homeostasis.

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PLoS genetics , 16 , 3 ,

PMID: 32191694

Open Access

Editorial: Autophagy and Ageing: Ideas, Methods, Molecules.
Proikas-Cezanne T, Ktistakis NT

Ever since it was first discussed in evolutionary terms by Haldane (1941), Medawar (1952), and Williams (1957), [reviewed in Partridge and Gems (2006)] aging has become a focus of much current research interest, especially following discoveries pointing to molecular, genetic, and biochemical hallmarks that control its progression and severity (López-Otín et al., 2013). Amongst the many cellular processes that provide physiological connections to the aging process, autophagy is perhaps one of the most compelling (Rubinsztein et al., 2011; Nakamura and Yoshimori, 2018).

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Frontiers in cell and developmental biology , 8 , 1 ,

PMID: 32185175

Open Access

Epigenetic changes occur at decidualisation genes as a function of reproductive ageing in mice.
Woods L, Morgan N, Zhao X, Dean W, Perez-Garcia V, Hemberger M

Reproductive decline in older female mice can be attributed to a failure of the uterus to decidualise in response to steroid hormones. Here, we show that normal decidualisation is associated with significant epigenetic changes. Notably, we identify a cohort of differentially methylated regions (DMRs), most of which gain DNA methylation between the early and late stages of decidualisation. These DMRs are enriched at progesterone-responsive gene loci that are essential for reproductive function. In female mice nearing the end of their reproductive lifespan, DNA methylation fidelity is lost at a number of CpG islands (CGIs) resulting in CGI hypermethylation at key decidualisation genes. Importantly, this hypermethylated state correlates with the failure of the corresponding genes to become transcriptionally upregulated during the implantation window. Thus, age-associated DNA methylation changes may underlie the decidualisation defects that are a common occurrence in older females. Alterations to the epigenome of uterine cells may therefore contribute significantly to the reproductive decline associated with advanced maternal age.

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Development (Cambridge, England) , 147 , 6 ,

PMID: 32184271

Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors.
Lochhead PA, Tucker JA, Tatum NJ, Wang J, Oxley D, Kidger AM, Johnson VP, Cassidy MA, Gray NS, Noble MEM, Cook SJ

The dual protein kinase-transcription factor, ERK5, is an emerging drug target in cancer and inflammation, and small-molecule ERK5 kinase inhibitors have been developed. However, selective ERK5 kinase inhibitors fail to recapitulate ERK5 genetic ablation phenotypes, suggesting kinase-independent functions for ERK5. Here we show that ERK5 kinase inhibitors cause paradoxical activation of ERK5 transcriptional activity mediated through its unique C-terminal transcriptional activation domain (TAD). Using the ERK5 kinase inhibitor, Compound 26 (ERK5-IN-1), as a paradigm, we have developed kinase-active, drug-resistant mutants of ERK5. With these mutants, we show that induction of ERK5 transcriptional activity requires direct binding of the inhibitor to the kinase domain. This in turn promotes conformational changes in the kinase domain that result in nuclear translocation of ERK5 and stimulation of gene transcription. This shows that both the ERK5 kinase and TAD must be considered when assessing the role of ERK5 and the effectiveness of anti-ERK5 therapeutics.

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Nature communications , 11 , 1 ,

PMID: 32170057

Open Access

Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium.
Kazakevych J, Denizot J, Liebert A, Portovedo M, Mosavie M, Jain P, Stellato C, Fraser C, Corrêa RO, Célestine M, Mattiuz R, Okkenhaug H, Miller JR, Vinolo MAR, Veldhoen M, Varga-Weisz P

How intestinal epithelial cells interact with the microbiota and how this is regulated at the gene expression level are critical questions. Smarcad1 is a conserved chromatin remodeling factor with a poorly understood tissue function. As this factor is highly expressed in the stem and proliferative zones of the intestinal epithelium, we explore its role in this tissue.

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Genome biology , 21 , 1 ,

PMID: 32160911

Open Access

Programmed axon degeneration: from mouse to mechanism to medicine.
Coleman MP, Höke A

Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (Wld) mouse, research has generated extensive knowledge of the molecular mechanisms underlying Wallerian degeneration, demonstrated its involvement in non-injury disorders and found multiple ways to block it. Recent developments have included: the detection of NMNAT2 mutations that implicate Wallerian degeneration in rare human diseases; the capacity for lifelong rescue of a lethal condition related to Wallerian degeneration in mice; the discovery of 'druggable' enzymes, including SARM1 and MYCBP2 (also known as PHR1), in Wallerian pathways; and the elucidation of protein structures to drive further understanding of the underlying mechanisms and drug development. Additionally, new data have indicated the potential of these advances to alleviate a number of common disorders, including chemotherapy-induced and diabetic peripheral neuropathies, traumatic brain injury, and amyotrophic lateral sclerosis.

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Nature reviews. Neuroscience , 1 , 1 ,

PMID: 32152523

The enigma of DNA methylation in the mammalian oocyte.
Demond H, Kelsey G

The mammalian genome experiences profound setting and resetting of epigenetic patterns during the life-course. This is understood best for DNA methylation: the specification of germ cells, gametogenesis, and early embryo development are characterised by phases of widespread erasure and rewriting of methylation. While mitigating against intergenerational transmission of epigenetic information, these processes must also ensure correct genomic imprinting that depends on faithful and long-term memory of gamete-derived methylation states in the next generation. This underscores the importance of understanding the mechanisms of methylation programming in the germline. methylation in the oocyte is of particular interest because of its intimate association with transcription, which results in a bimodal methylome unique amongst mammalian cells. Moreover, this methylation landscape is entirely set up in a non-dividing cell, making the oocyte a fascinating model system in which to explore mechanistic determinants of methylation. Here, we summarise current knowledge on the oocyte DNA methylome and how it is established, focussing on recent insights from knockout models in the mouse that explore the interplay between methylation and chromatin states. We also highlight some remaining paradoxes and enigmas, in particular the involvement of non-nuclear factors for correct methylation.

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F1000Research , 9 , 1 ,

PMID: 32148772

Open Access

IRF4 instructs effector Treg differentiation and immune suppression in human cancer.
Alvisi G, Brummelman J, Puccio S, Mazza EMC, Paoluzzi Tomada E, Losurdo A, Zanon V, Peano C, Colombo FS, Scarpa A, Alloisio M, Vasanthakumar A, Roychoudhuri R, Kallikourdis M, Pagani M, Lopci E, Novellis P, Blume J, Kallies A, Veronesi G, Lugli E

The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ regulatory T cells (Tregs) in tumors are poorly known. High-dimensional single cell profiling of T cells from chemotherapy-naïve individuals with non-small cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity. In contrast to the IRF4- counterparts, IRF4+ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespectively of the tumor type.

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The Journal of clinical investigation , 1 , 1 ,

PMID: 32125291

Open Access

LPIAT, a -Phosphatidylinositol Acyltransferase, Modulates Seed Germination in through PIP Signalling Pathways and is Involved in Hyperosmotic Response.
Coulon D, Faure L, Grison M, Pascal S, Wattelet-Boyer V, Clark J, Guedard ML, Testet E, Bessoule JJ

-lipid acyltransferases are enzymes involved in various processes such as lipid synthesis and remodelling. Here, we characterized the activity of an acyltransferase from (LPIAT). In vitro, this protein, expressed in membrane, displayed a 2--phosphatidylinositol acyltransferase activity with a specificity towards saturated long chain acyl CoAs (C16:0- and C18:0-CoAs), allowing the remodelling of phosphatidylinositol. , gene was expressed in mature seeds and very transiently during seed imbibition, mostly in aleurone-like layer cells. Whereas the disruption of this gene did not alter the lipid composition of seed, its overexpression in leaves promoted a strong increase in the phosphatidylinositol phosphates (PIP) level without affecting the PIP2 content. The spatial and temporal narrow expression of this gene as well as the modification of PIP metabolism led us to investigate its role in the control of seed germination. Seeds from the mutant germinated faster and were less sensitive to abscisic acid (ABA) than wild-type or overexpressing lines. We also showed that the protective effect of ABA on young seedlings against dryness was reduced for line. In addition, germination of mutant seeds was more sensitive to hyperosmotic stress. All these results suggest a link between phosphoinositides and ABA signalling in the control of seed germination.

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International journal of molecular sciences , 21 , 5 ,

PMID: 32121266

Open Access

Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection.
Casanova V, Sousa FH, Shakamuri P, Svoboda P, Buch C, D'Acremont M, Christophorou MA, Pohl J, Stevens C, Barlow PG

Human rhinoviruses (HRV) are the most common cause of viral respiratory tract infections. While normally mild and self-limiting in healthy adults, HRV infections are associated with bronchiolitis in infants, pneumonia in immunocompromised patients, and exacerbations of asthma and COPD. The human cathelicidin LL-37 is a host defense peptide (HDP) with broad immunomodulatory and antimicrobial activities that has direct antiviral effects against HRV. However, LL-37 is known to be susceptible to the enzymatic activity of peptidyl arginine deiminases (PAD), and exposure of the peptide to these enzymes results in the conversion of positively charged arginines to neutral citrullines (citrullination). Here, we demonstrate that citrullination of LL-37 reduced its direct antiviral activity against HRV. Furthermore, while the anti-rhinovirus activity of LL-37 results in dampened epithelial cell inflammatory responses, citrullination of the peptide, and a loss in antiviral activity, ameliorates this effect. This study also demonstrates that HRV infection upregulates PAD2 protein expression, and increases levels of protein citrullination, including histone H3, in human bronchial epithelial cells. Increased gene expression and HDP citrullination during infection may represent a novel viral evasion mechanism, likely applicable to a wide range of pathogens, and should therefore be considered in the design of therapeutic peptide derivatives.

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Frontiers in immunology , 11 , 1 ,

PMID: 32117246

Open Access