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Ahmed, S.

Publications and source records attributed to Ahmed, S..

At least 145 records · Page 8Linked to original sources
bioRxiv2019

Menstrual hygiene management practice and factors affecting it among high school females in Ambo City, Oromia state, Ethiopia, 2018: A cross-sectional mixed method.

I.BackgroundThough menstruation is normal physiology in the females life, if not managed safely, it can interrupt daily activity or it may lead to health problems. Poor water, sanitation and hygiene (WASH) facilities in schools, inadequate puberty education and lack of hygienic menstrual hygiene management items (absorbents) cause girls to experience menstruation as shameful and uncomfortable. This study aimed to assess the extent of unsafe menstrual hygiene practice and factors influencing it among school females in Ambo, Ethiopia.\n\nMethodsan institutional-based mixed-method cross-sectional study was conducted from March 01 to 15/2018 to collect data from 364 school females, teachers, and investigators observation. To collect the data, self-administered technique, interview, observational and FGD techniques were used. Data were analyzed using SPSS statistical software version 20. Uni-variate, bivariate and multiple logistic regression analysis were done. With 95% CI, the P-value of less than 0.05 was taken as the level of significance.\n\nResultsthe prevalence of the unsafe menstrual hygiene management practice was 53.6%, which implies urgent response from the stakeholders is of paramount importance. Factors such as the age of the females, frequency of discussing menses with mothers and source of information about menses were variables significantly associated with menstrual hygiene management practice.\n\nConclusion and RecommendationHigh numbers of school females menstrual hygiene management were poorly managed. This implies urgent measure is needed from the stakeholders to solve these problems so that sustainable development goal number 3, 4 and 5 will be achieved. To rid off the current problems which school females are facing, comprehensive and different sectors collaboration is important. Specifically, education sectors, water and sanitation sectors, and health sectors bear the frontline responsibilities.

developmental biology↗
bioRxiv2019

Mutations in the SPTLC1 gene are a cause of amyotrophic lateral sclerosis that may be amenable to serine supplementation

Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of childhood motor disorder with a heterogeneous clinical presentation. The underlying causes of this condition are poorly understood, hindering the development of effective therapies. In a whole-exome sequencing trio-family study of three unrelated juvenile patients diagnosed with ALS and failure to thrive, we identified de-novo mutations in SPTLC1 (p.Ala20Ser in two patients and p.Ser331Tyr) not present in their healthy parents or siblings. SPTLC1 encodes a subunit of the serine palmitoyltransferase complex, a key enzyme in sphingolipid biosynthesis. Mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A, with a characteristic increase in plasma levels of neurotoxic deoxymethyl-sphinganine. We found an increase of this metabolite in one of our patients carrying the p.Ala20Ser mutation. Treatment of one of the patients with high dose, oral L-serine led to an increase in body weight, suggesting that serine supplementation may be beneficial among patients carrying mutations in this gene.

genetics↗
bioRxiv2019

Genetic modifiers of risk and age at onset in GBA associated Parkinson disease and Lewy body dementia

Parkinsons disease (PD) is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of PD, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as PD and Lewy body dementia (LBD). These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known PD risk variants.\n\nUsing multiple, large case-control datasets, totalling 217,165 individuals (22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls), we identified 1,772 PD cases, 711 proxy cases and 7,624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent PD-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall PD genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S neurons were shown to have decreased Cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated PD risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have important implications for selection of GBA carriers for therapeutic interventions.

genetics↗
bioRxiv2019

POT-1 telomere binding protein promotes a novel form of Transgenerational Epigenetic Inheritance

Transgenerational Epigenetic Inheritance occurs when gametes transmit forms of information without altering genomic DNA1. Although deficiency for telomerase in human families causes transgenerational shortening of telomeres2, a role for telomeres in Transgenerational Epigenetic Inheritance is unknown. Here we show that Protection Of Telomeres 1 (Pot1) proteins, which interact with single-stranded telomeric DNA3,4, function in gametes to regulate developmental expression of telomeric foci for multiple generations. C. elegans POT-1 and POT-25,6 formed abundant telomeric foci in adult germ cells that vanished in 1-cell embryos and gradually accumulated during development. pot-2 mutants displayed abundant POT-1::mCherry foci throughout development. pot-2 mutant gametes created F1 cross-progeny with constitutively abundant POT-1::mCherry and mNeonGreen::POT-2 foci, which persisted for 6 generations but did not alter telomere length. pot-1 mutant and pot-2; pot-1 double mutant gametes gave rise to progeny with constitutively diminished Pot1 foci. Genomic silencing and small RNAs potentiate many transgenerational effects7 but did not affect Pot1 foci. We conclude that C. elegans POT-1 functions at telomeres of pot-2 mutant gametes to create constitutively high levels of Pot1 foci in future generations. As regulation of telomeres and Pot1 have been tied to cancer8,9, this novel and highly persistent form of Transgenerational Epigenetic Inheritance could be relevant to human health.

genetics↗
bioRxiv2019

Feedback regulation of BMP signaling by C. elegans cuticle collagens

Cellular responsiveness to environmental cues, including changes in extracellular matrix (ECM), is critical for normal processes such as development and wound healing, but can go awry, as in oncogenesis and fibrosis. One type of molecular pathway allowing this responsiveness is the bone morphogenetic protein (BMP) signaling pathway. Due to their broad and potent functions, BMPs and their signaling pathways are highly regulated at multiple levels. In Caenorhabditis elegans, the BMP ligand DBL-1 is a major regulator of body size. We have previously shown that DBL-1/BMP signaling determines body size through transcriptional regulation of cuticle collagen genes. We have now obtained evidence of feedback regulation of DBL-1/BMP by collagen genes. We analyzed four DBL-1-regulated collagen genes that affect body size. Here we show that inactivation of any one of these cuticle collagen genes reduces DBL-1/BMP signaling, as measured by a Smad activity reporter. Furthermore, we find that depletion of these collagens reduces GFP::DBL-1 fluorescence, and acts unexpectedly at the level of dbl-1 transcription. We therefore conclude that cuticle, a type of ECM, impinges on DBL-1/BMP expression and signaling. In contrast to other characterized examples, however, the feedback regulation of DBL-1/BMP signaling by collagens is likely to be contact-independent, due to the physical separation of the cuticle from DBL-1-expressing cells in the ventral nerve cord. Our results provide an entry point into a novel mechanism of regulation of BMP signaling, with broader implications for mechanical regulation of gene expression in general.

developmental biology↗
bioRxiv2019

Integration of a FT expression cassette into CRISPR/Cas9 construct enables fast generation and easy identification of transgene-free mutants in Arabidopsis

The CRISPR/Cas9 genome editing technique has been widely used to generate transgene-free mutants in different plant species. Several different methods including fluorescence marker-assisted visual screen of transgene-free mutants and programmed self-elimination of CRISPR/Cas9 construct have been use to increase the efficiency of genome edited transgene-free mutants isolation, but the overall time length required to obtain transgene-free mutants has remained unchanged in these methods. We report here a method for fast generation and easy identification of transgene-free mutants in Arabidopsis. By generating and using a single FT expression cassette-containing CRISPR/Cas9 construct, we targeted two sites of the AITR1 gene. We obtained many early bolting plants in T1 generation, and found that about two thirds of these plants have detectable mutations. We then analyzed T2 generations of two representative lines of genome edited early bolting T1 plants, and identified plants without early bolting phenotype, i.e., transgene-free plants, for both lines. Further more, homologues aitr1 mutants were successful obtained for both lines from these transgene-free plants. Taken together, these results suggest that the method described here enables fast generation, and at the mean time, easy identification of transgene-free mutants in plants.

plant biology↗
bioRxiv2019

The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

BackgroundThe Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.\n\nObjectivesTo perform the largest Parkinson disease (PD) genome-wide association study (GWAS) restricted to a single country.\n\nMethodsWe performed a GWAS for both risk of PD and age-at-onset (AAO) in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations and burden analyses.\n\nResultsWe identified a novel population-specific GWAS signal at PARK2 associated with AAO. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence via two-sample Mendelian randomization in expression and methylation datasets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.\n\nConclusionsOur data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain.

neuroscience↗
bioRxiv2019

Telomeric small RNAs in the genus Caenorhabditis

Telomeric DNA is composed of simple tandem repeat sequences and has a G-rich strand that runs 5 to 3 towards the chromosome terminus. Small RNAs with homology to telomeres have been observed in several organisms and could originate from telomeres or from interstitial telomere sequences (ITSs), which are composites of degenerate and perfect telomere repeat sequences found on chromosome arms. We identified C. elegans small RNAs composed of the Caenorhabditis telomere sequence (TTAGGC)n with up to three mismatches, which might interact with telomeres. We rigorously defined ITSs for genomes of C. elegans and for two closely related nematodes, C. briggsae and C. remanei. We found that most telomeric small RNAs with mismatches originated from ITSs, which were depleted from mRNAs and but were enriched in introns whose genes often displayed hallmarks of genomic silencing. C. elegans small RNAs composed of perfect telomere repeats were very rare but were increased by several orders of magnitude in C. briggsae and C. remanei. Major small RNA species in C. elegans begin with a 5 guanine nucleotide, which was strongly depleted from perfect telomeric small RNAs of all three Caenorhabditis species. Perfect telomeric small RNAs corresponding to the G-rich strand of the telomere commonly began with 5 UAGGCU and 5UUAGGC, whereas C-rich strand RNAs commonly begin with 5CUAAGC. In contrast, telomeric small RNAs with mismatches had a mixture of all four 5 nucleotides. Together, our results imply that perfect telomeric small RNAs have a mechanism of biogenesis that is distinct from known classes of small RNAs and that a dramatic change in their regulation occurred during recent Caenorhabditis evolution.

genomics↗
bioRxiv2019

A model for estimating traction force magnitude reveals differential regulation of actomyosin activity and matrix adhesion number in response to smooth muscle cell spreading

Decreased aortic compliance is associated with ageing and vascular disease, including atherosclerosis and hypertension. Ultimately, changes in aortic compliance are driven by altered ECM composition however, recent findings have identified a cellular component to decreased aortic compliance observed in ageing and hypertension. Vascular smooth muscle cells (VSMCs) line the blood vessel wall and VSMC contraction regulates vascular tone and contributes to aortic compliance. Mechanical cues derived from the ECM influence VSMC function, yet whether ECM rigidity influences VSMC force generation remains unclear. In this study, we describe the relationship between VSMC spreading, traction force magnitude and matrix rigidity. Importantly, we show that spreading predicts integrated traction force (integrated-TF) magnitude independently of matrix rigidity. Using linear regression analysis, we have generated a model for calculating integrated-TF from VSMC area. This model closely predicts the integrated traction force measured by live VSMC traction force microscopy. Vinculin staining analysis revealed that spreading strongly correlated with adhesion number per VSMC, suggesting that increased VSMC integrated-TF was due to enhanced matrix anchor points. Further analysis revealed that calculated integrated-TF per adhesion was reduced by matrix rigidity, however, adhesion number/m2 increased, resulting in the average integrated-TF/m2 remaining unaltered. As a result, the integrated-TF/VSMC spreading relationship is independent of matrix rigidity. Therefore, our study has identified and validated a novel model to predict and understand the mechanisms influencing VSMC traction force magnitude.

cell biology↗
bioRxiv2019

A genome-wide screen for ER autophagy highlights key roles of mitochondrial metabolism and ER- resident UFMylation

Selective degradation of organelles via autophagy is critical for cellular differentiation, homeostasis, and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathy but is poorly understood beyond a few specialized autophagosomal receptors and remodelers. Using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence factors involved in human ER-phagy. We mechanistically investigated two pathways unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ER-phagy, which reverses the logic of general autophagy. Mitochondrial crosstalk with ER-phagy bypasses the energy sensor AMPK, instead directly impacting ULK1. Second, ER-localized UFMylation is required for ER-phagy that represses the unfolded protein response. The UFL1 ligase is brought to the ER surface by DDRGK1, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the unique cellular logic of ER-phagy, reveal parallels between organelle autophagies, and provide an entry point to the relatively unexplored process of degrading the ER network.

cell biology↗
bioRxiv2019

Investigation of the effect of estradiol and subculturing on the receptor expression within hormone-dependent breast cancer cells

It is now known that a very crucial role in breast cancer development, prognosis and occurrence is played by the estrogen receptor (ER). The steroid hormone estradiol (E2) acts via two nuclear receptors, estrogen receptor- (ER) and estrogen receptor-{beta} (ER{beta}). E2 was shown previously to increase breast cancer cell proliferation in a dose-dependent manner and also induce apoptosis in long term estrogen deprived breast cancer cells. Studies have also shown that the degree of subculturing affects cell line property including gene expression. The aim of this study was to investigate the effect of E2 concentration on cell proliferation, morphology and ER expression and to investigate the effect of subculturing on the expression of ER. Our results have shown that an increase in E2 concentration was found to increase MCF-7 cell proliferation, but extreme concentrations caused significantly low cell proliferation and induced apoptosis. Moreover, ER expression was significantly upregulated with an increase in E2 concentration, whereas ER{beta}2 expression was found to be unchanged at low E2 concentration and significantly upregulated at higher E2 concentration. ER expression at passage 3 ([E2]=1nM) was significantly downregulated compared to the cells at passage 0, in addition to the significant downregulation of the same at E2 concentrations of 1nM and 10{micro}M compared to the untreated control sample. Overall, our data suggests that high concentration of E2 can reduce proliferation and induce apoptosis in the breast cancer cells. Increased E2 exposure and subculturing also appear to change the ER expression significantly in the breast cancer cell line.

cancer biology↗
bioRxiv2019

NORTH: a highly accurate and scalable Naive Bayes based ORTHologous gene clustering algorithm

BackgroundThe principal objective of comparative genomics is inferring attributes of an unknown gene by comparing it with well-studied genes. In this regard, identifying orthologous genes plays a pivotal role as the orthologous genes remain less diverged in the course of evolution. However, identifying orthologous genes is often difficult, slow, and idiosyncratic, especially in the presence of multiplicity of domains in proteins, evolutionary dynamics (gene duplication, transfer, loss, introgression etc.), multiple paralogous genes, incomplete genome data, and for distantly related species where similarity is hard to recognize. MotivationAdvances in identifying orthologs have mostly been constrained to developing databases of genes or methods which involve computationally expensive BLAST search or constructing phylogenetic trees to infer orthologous relationships. These methods do not generally scale well and cannot analyze large amount of data from diverse organisms with high accuracy. Moreover, most of these methods involve manual parameter tuning, and hence are neither fully automated nor free from human bias. ResultsWe present NORTH, a novel, automated, highly accurate and scalable machine learning based orhtologous gene clustering method. We have utilized the biological basis and intuition of orthologous genes and made an effort to incorporate appropriate ideas from machine learning (ML) and natural language processing (NLP). We have discovered that the BLAST search based protocols deeply resemble a "text classification" problem. Thus, we employ the robust bag-of-words model accompanied by a Naive Bayes classifier to cluster the orthologous genes. We studied 1,255,877 genes in the largest 250 ortholog clusters from the KEGG database, across 3,880 organisms comprising the six major groups of life, namely, Archaea, Bacteria, Animals, Fungi, Plants and Protists. Despite having more than a million of genes on distantly related species with acute data imbalance, NORTH is able to cluster them with 98.48% Precision, 98.43% Recall and 98.44% F1 score, showing that automatic orthologous gene clustering can be both highly accurate and scalable. NORTH is available as a web interface with a server side application, along with cross-platform native applications (available at https://nibtehaz.github.io/NORTH/) - allowing queries based on individual genes.

bioinformatics↗
bioRxiv2018

Prohibitin is a prognostic marker of relapse and therapeutic target to block chemotherapy resistance in Wilms tumor

Wilms tumor (WT) is the most common childhood kidney cancer. To improve risk stratification and identify novel therapeutic targets for patients with WT, we used high-resolution mass spectrometry proteomics to identify urine tumor markers associated with WT relapse. We determined urine proteomes at diagnosis of 49 patients with WT, non-WT renal tumors, and age-matched controls, leading to the quantitation of 6,520 urine proteins. Supervised analysis revealed specific urine markers of renal rhabdoid tumors, kidney clear cell sarcomas, renal cell carcinomas, as well as those detected in cured and relapsed WT. In particular, urine prohibitin was significantly elevated at diagnosis in patients with relapsed as compared to cured WT. In a validation cohort of 139 patients, a specific urine prohibitin enzyme-linked immunosorbent assay demonstrated that prohibitin concentrations greater than 998 ng/mL at diagnosis were significantly associated with ultimate WT relapse. Immunohistochemical analysis revealed that prohibitin was highly expressed in primary WT specimens and associated with disease stage. Using functional genetic experiments, we found that prohibitin was required for the growth and survival of WT cells. Overexpression of prohibitin was sufficient to block intrinsic mitochondrial apoptosis and to cause resistance to diverse chemotherapy drugs, at least in part by dysregulating factors that control apoptotic cytochrome c release from mitochondrial cristae. Thus, urine prohibitin may improve therapy stratification, non-invasive monitoring of treatment response and early disease detection. In addition, therapeutic targeting of chemotherapy resistance induced by prohibitin dysregulation may offer improved therapies for patients with Wilms and other relapsed or refractory tumors.

cancer biology↗
bioRxiv2018

Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems

Guiding the dose selection for monoclonal antibody oncology drugs is often done using methods for predicting the receptor occupancy of the drug in the tumor. In this manuscript, previous work on characterizing target inhibition at steady state using the AFIR metric [1] is extended to include a \"target-tissue\" compartment and the shedding of membrane-bound targets. A new potency metric AFTIR (Averarge Free Tissue target to Initial target ratio at steady state) is derived, and it depends on only four key quantities: the equilibrium binding constant, the fold-change in target expression at steady state after binding to drug, the biodistribution of target from circulation to target tissue, and the average drug concentration in circulation. The AFTIR metric is useful for guiding dose selection, for efficiently performing sensitivity analyses, and for building intuition for more complex target mediated drug disposition models. In particular, reducing the complex, physiological model to four key parameters needed to predict target inhibition helps to highlight specific parameters that are the most important to estimate in future experiments to guide drug development.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC=\"FIGDIR/small/432500_fig1.gif\" ALT=\"Figure 1\">\nView larger version (30K):\norg.highwire.dtl.DTLVardef@6895d7org.highwire.dtl.DTLVardef@4566e0org.highwire.dtl.DTLVardef@6515e8org.highwire.dtl.DTLVardef@8168ea_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 1C_FLOATNO Graphical Abstract\n\nC_FIG

pharmacology and toxicology↗
bioRxiv2018

Unified single-cell analysis of testis gene regulation and pathology in 5 mouse strains

By removing the confounding factor of cellular heterogeneity, single cell genomics can revolutionize the study of development and disease, but methods are needed to simplify comparison among individuals. To develop such a framework, we assayed the transcriptome in 62,600 single cells from the testes of wildtype mice, and mice with gonadal defects due to disruption of the genes Mlh3, Hormad1, Cul4a or Cnp. The resulting expression atlas of distinct cell clusters revealed novel markers and new insights into testis gene regulation. By jointly analysing mutant and wildtype cells using a model-based factor analysis method, SDA, we decomposed our data into 46 components that identify novel meiotic gene regulatory programmes, mutant-specific pathological processes, and technical effects. Moreover, we identify, de novo, DNA sequence motifs associated with each component, and show that SDA can be used to impute expression values from single cell data. Analysis of SDA components also led us to identify a rare population of macrophages within the seminiferous tubules of Mlh3-/- and Hormad1-/- testes, an area typically associated with immune privilege. We provide a web application to enable interactive exploration of testis gene expression and components at http://www.stats.ox.ac.uk/~wells/testisAtlas.html

genomics↗
bioRxiv2018

DAF-16/Foxo suppresses the transgenerational sterility of prg-1 piRNA mutants via a systemic small RNA pathway

Mutation of the daf-2 insulin/IGF-1 receptor activates the DAF-16/Foxo transcription factor to suppress the transgenerational sterility phenotype of prg-1/piRNA mutants that are deficient for piRNA-mediated genome silencing. As with PRG-1/piRNAs, mutations in the nuclear RNA interference gene nrde-1 compromised germ cell immortality, but deficiency for daf-2 did not suppress the transgenerational sterility of nrde-1 or nrde-4 single mutants or of prg-1; nrde-4 or prg-1; hrde-1 double mutants. NRDE-1 and NRDE-4 promote transcriptional silencing in somatic cells via the nuclear Argonaute protein NRDE-3, which was dispensable for germ cell immortality. However, daf-2 deficiency failed to promote germ cell immortality in prg-1; nrde-3 mutants. Consistently, we found that DAF-16 activity in somatic cells suppressed the transgenerational sterility of prg-1 mutants via the SID-1 dsRNA transmembrane channel that promotes systemic RNAi as well as Dicer, the dsRNA binding protein RDE-4 and the RDRP RRF-3. We conclude that DAF-16 activates a cell-non-autonomous systemic RNAi pathway that promotes small RNA-mediated genome silencing in germ cells to suppress loss of the genomic immune surveillance factor Piwi/PRG-1. Author SummarySmall RNAs can promote genome silencing. The Argonaute protein Piwi interacts with thousands of small RNAs termed piRNAs in germ cells to suppress expression of transposons and foreign genetic elements. However, the Piwi silencing system may be commonly targeted by viral or transposon genomic parasites that seek to suppress the endogenous defences against their expression and replication. Activation of the DAF-16 stress response pathway promotes adult longevity and can also abolish the transgenerational sterility of C. elegans Piwi mutants. We found that DAF-16 accomplishes this by activating a somatic small RNA pathway where small RNAs are initially produced in the soma and are then transported into the germline to suppress expression of a toxic genetic locus in Piwi mutants. Thus, the DAF-16 stress response pathway activates a systemic small RNA cascade to suppress defects in the Piwi/piRNA genome silencing system.

genetics↗
bioRxiv2018

Deficiency for Piwi results in transmission of a heritable stress that promotes longevity via DAF-16/Foxo

The C. elegans Argonaute protein PRG-1/Piwi and associated piRNAs protect metazoan genomes by silencing transposons and other types of foreign DNA. As prg-1 mutants are propagated, their fertility deteriorates prior to the onset of a reproductive arrest phenotype that resembles a starvation-induced stress response. We found that late-generation prg-1 mutants with substantially reduced fertility were long-lived, whereas early- or mid-generation prg-1 mutants had normal lifespans. Loss of the stress response transcription factor DAF-16 caused mid- or late-generation prg-1 mutants to live very short lives, whereas overexpression of DAF-16 enabled both mid- and late-generation prg-1 mutants to live long. Cytoplasmic P-bodies that respond to stress increased in long-lived late-generation prg-1 mutants and were transmitted to F1 but not F2 cross-progeny. Moreover, moderate levels of heritable stress shorten late-generation prg-1 mutant longevity when DAF-16 or P bodies are deficient. Together, these results suggest that the longevity of late-generation prg-1 mutants is a hormetic stress response. However, dauer larvae that occur in response to stress were not observed in late-generation prg-1 mutants. Small germ cell nucleoli that depended on germline DAF-16 were present in late-generation prg-1 mutants but were not necessary for their longevity. We propose that prg-1 mutant germ cells transmit a form of heritable stress, high levels of which promote longevity and strongly reduce fertility. The heritable stress transmitted by PRG-1/Piwi mutant germ cells may be generally relevant to epigenetic inheritance of longevity. Core message of paperprg-1/Piwi mutants with strongly reduced fertility live long and longevity is transmitted for one generation to F1 cross progeny. Stress granules are increased and germ cell nucleoli are small for long-lived Piwi mutants and their F1 progeny. Loss of daf-16 stress response transcription factor or dcap-1 P body protein causes very short life for worms when prg-1 mutant fertility is moderately reduced, whereas moderate fertility is sufficient to extend lifespan when somatic DAF-16 is overexpressed. We propose that prg-1 mutant germ cells transmit a heritable epigenetic factor that is stressful and elicits two hormetic stress responses: reproductive arrest and longevity.

genetics↗
bioRxiv2018

Transgenerational sterility of small RNA genome silencing mutants in response to germ granule dysfunction

In several species, Piwi/piRNA genome silencing defects lead to immediate sterility accompanied by heterochromatin dysfunction and transposon-induced genomic instability, which may cause Piwi mutant sterility. In C. elegans, Piwi pathway mutants transmit a heritable stress through germ cells that induces sterility after growth for several generations. We found that sterile Piwi pathway mutant germ cells displayed inconsistent increases in DNA damage but consistently altered perinuclear germ granules that are known to promote fertility. Germ granule dysfunction did not elicit transposon expression but was sufficient to induce multiple phenotypes found in sterile Piwi silencing mutants, including germline atrophy and regrowth. Furthermore, loss of the germ granule component PGL-1 accelerated sterility in response to deficiency for prg-1/Piwi. Restoration of germ granule function to sterile pgl-1 mutants restored their fertility. Together, our results suggest that germ granule defects may promote an adult reproductive arrest phenotype that is responsible for Piwi/piRNA mutant sterility.

developmental biology↗