There is accumulating evidence to show that environmental stressors can regulate a variety of phenotypes in descendants through germline-mediated epigenetic inheritance. Studies of model organisms exposed to environme...There is accumulating evidence to show that environmental stressors can regulate a variety of phenotypes in descendants through germline-mediated epigenetic inheritance. Studies of model organisms exposed to environmental cues(e.g., diet, heat stress, toxins) indicate that altered DNA methylations, histone modifications, or non-coding RNAs in the germ cells are responsible for the transgenerational effects. In addition,it has also become evident that maternal provision could provide a mechanism for the transgenerational inheritance of stress adaptations that result from ancestral environmental cues. However, how the signal of environmentally-induced stress response transmits from the soma to the germline, which may influence offspring fitness, remains largely elusive. Small RNAs could serve as signaling molecules that transmit between tissues and even across generations. Furthermore, a recent study revealed that neuronal mitochondrial perturbations induce a transgenerational induction of the mitochondrial unfolded protein response mediated by a Wnt-dependent increase in mitochondrial DNA levels. Here, we review recent work on the molecular mechanism by which parental experience can affect future generations and the importance of soma-to-germline signaling for transgenerational inheritance.展开更多
Consumption of fried foods is highly prevalent in the Western dietary pattern.Western diet has been unfavorably linked with high risk of developing cardiovascular diseases.Heart failure(HF)as a cardiovascular disease ...Consumption of fried foods is highly prevalent in the Western dietary pattern.Western diet has been unfavorably linked with high risk of developing cardiovascular diseases.Heart failure(HF)as a cardiovascular disease subtype is a growing global pandemic with high morbidity and mortality.However,the causal relationship between long-term fried food consumption and incident HF remains unclear.Our population-based study revealed that frequent fried food consumption is strongly associated with 15%higher risk of HF.The causal relationship may be ascribed to the dietary acrylamide exposure in fried foods.Further cross-sectional study evidenced that acrylamide exposure is associated with an increased risk of HF.Furthermore,we discover and demonstrate that chronic acrylamide exposure may induce HF in zebrafish and mice.Mechanistically,we reveal that acrylamide induces energy metabolism disturbance in heart due to the mitochondria dysfunction and metabolic remodeling.Moreover,acrylamide exposure induces myocardial apoptosis via inhibiting NOTCH1-phosphatidylinositol 3-kinase/AKT signaling.In addition,acrylamide exposure could affect heart development during early life stage,and the adverse effect of acrylamide exposure is a threat for next generation via epigenetic change evoked by DNA methyltransferase 1(DNMT1).In this study,we reveal the adverse effects and underlying mechanism of fried foods and acrylamide as a typical food processing contaminant on HF from population-based observations to experimental validation.Collectively,these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered HF and highlight the significance of reducing fried food consumption for lower the risk of HF.展开更多
Mental illness remains the greatest chronic health burden globally with few inroads having been made despite significant advances in genomic knowledge in recent decades.The field of psychiatry is constantly challenged...Mental illness remains the greatest chronic health burden globally with few inroads having been made despite significant advances in genomic knowledge in recent decades.The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations,and that has to be supported by a continuous growth in knowledge.The majority of neuropsychiatric symptoms reflect complex geneenvironment interactions,with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms.It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stressrelated behavioural phenotypes in both paternal and maternal lineages,providing further supporting evidence for heritability in humans.However,unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions.While rodents will remain the dominant model system for preclinical studies(especially for addressing complex behavioural phenotypes),there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models.Here,we will discuss the utility and advantages of two alternative model organisms–Caenorhabditis elegans and Drosophila melanogaster-and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.展开更多
Background In the current context of global warming,thermal manipulation of avian embryos has received increasing attention as a strategy to promote heat tolerance in avian species by simply increasing the egg incubat...Background In the current context of global warming,thermal manipulation of avian embryos has received increasing attention as a strategy to promote heat tolerance in avian species by simply increasing the egg incubation temperature.However,because of their likely epigenetic origin,thermal manipulation effects may last more than one generation with consequences for the poultry industry.In this work,a multigenerational and transgenerational analysis of thermal manipulation during embryogenesis was performed to uncover the long-term effects of such procedure.Results Thermal manipulation repeated during 4 generations had an effect on hatchability,body weight,and weight of eggs laid in Japanese quails,with some effects increasing in importance over generations.Moreover,the effects on body weight and egg weight could be transmitted transgenerationally,suggesting non-genetic inheritance mechanisms.This hypothesis is reinforced by the observed reversion of the effect on growth after five unexposed generations.Interestingly,a beneficial effect of thermal manipulation on heat tolerance was observed a few days after hatching,but this effect was not transgenerational.Conclusions Our multigenerational study showed that thermal conditioning of quail embryos has a beneficial effect on post-hatch heat tolerance hampered by transgenerational but reversible defects on growth.Assuming that no genetic variability underlies these changes,this study provides the first demonstration of epigenetic inheritance of traits induced by environmental temperature modification associated with long-term impacts in an avian species.展开更多
Under the framework of classical genetics and Darwinian theory,DNA sequence variation has long been considered the sole driving force behind the formation of organismal traits.Species passively undergo natural selecti...Under the framework of classical genetics and Darwinian theory,DNA sequence variation has long been considered the sole driving force behind the formation of organismal traits.Species passively undergo natural selection through random DNA mutations,gradually adapting to their environments and sustaining their populations(Laland et al.,2014).However,epigenetic studies have revealed that certain traits or phenotypes caused by epigenetic modifications,such as DNA(de)methylation(without any DNA sequence change),can be inherited across generations—a phenomenon termed transgenerational epigenetic inheritance(TEI)(Fitz-James and Cavalli,2022).展开更多
An association between assisted reproductive technology （ART） and neurobehavioral imprinting disorders has been reported in many studies, and it seems that ART may interfere with imprint reprogramming. However, it h...An association between assisted reproductive technology （ART） and neurobehavioral imprinting disorders has been reported in many studies, and it seems that ART may interfere with imprint reprogramming. However, it has never been explored whether epigenetic erros or imprinting disease susceptibility induced by ART can be inherited transgenerationally. Hence, the aim of this study was to determine the effect of in vitro fertilization and embryo transfer （IVF-ET） on transgenerational inheritance in am inbred mouse model. Mice derived from IVF-ET were outcrossed to wild-type C57BL/6J to obtain their female and male line F2 and F3 generations. Their behavior, morphology, histology, and DNA methylation status at several important differentially methylated regions （DMRs） were analyzed by Morris water maze, hematoxylin and eosin （H＆E） staining, and bisulfite genomic sequencing. No significant differences in spatial learning or phenotypic abnormality were found in adults derived from IVF （F1） and female and male line F2 and F3 generations. A borderline trend of hypomethylation was found in H19 DMR CpG island 3 in the female line-derived F3 generation （0.40±0.118, P=0.086）. Methylation status in H19/Igf2 DMR island 1, Igf2 DMR, KvDMR, and Snrpn DMR displayed normal patterns. Methylation percentage did not differ significantly from that of adults conceived naturally, and the expression of the genes they regulated was not disturbed. Transgenerational integrity, such as behavior, morphology, histology, and DNA methylation status, was maintained in these generations, which indicates that exposure of female germ cells to hormonel stimulation and gamete manipulation might not affect the individuals and their descendents.展开更多
Plants exhibit remarkable abilities to learn,communicate,memorize,and develop stimulus-dependent decision-making circuits.Unlike animals,plant memory is uniquely rooted in cellular,molecular,and biochemical networks,l...Plants exhibit remarkable abilities to learn,communicate,memorize,and develop stimulus-dependent decision-making circuits.Unlike animals,plant memory is uniquely rooted in cellular,molecular,and biochemical networks,lacking specialized organs for these functions.Consequently,plants can effectively learn and respond to diverse challenges,becoming used to recurring signals.Artificial intelligence(AI)and machine learning(ML)represent the new frontiers of biological sciences,offering the potential to predict crop behavior under environmental stresses associated with climate change.Epigenetic mechanisms,serving as the foundational blueprints of plant memory,are crucial in regulating plant adaptation to envi-ronmental stimuli.They achieve this adaptation by modulating chromatin structure and acces-sibility,which contribute to gene expression regulation and allow plants to adapt dynam-ically to changing environmental conditions.In this review,we describe novel methods and approaches in AI and ML to elucidate how plant memory occurs in response to environmental stimuli and priming mechanisms.Furthermore,we explore innovative strategies exploiting transgenerational memory for plant breeding to develop crops resilient to multiple stresses.In this context,AI and ML can aid in integrating and analyzing epigenetic data of plant stress responses to optimize the training of the pa-rental plants.展开更多
The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons.Here we explored how gestational exposure to dexamethasone,a synthetic glucocorticoid commonly used in clinical practice,...The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons.Here we explored how gestational exposure to dexamethasone,a synthetic glucocorticoid commonly used in clinical practice,has lasting effects on offspring's learning and memory.Adult offspring rats of prenatal dexamethasone exposure(PDE)displayed significant impairments in novelty recognition and spatial learning memory,with some phenotypes maintained transgenerationally.PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations,and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory,but these changes failed to carry over to offspring of F5 and F7 generations.Mechanistically,altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission,which might be related to oocyte-specific high expression and transmission of miR-133a-3p.Together,PDE affects hippocampal excitatory synaptic transmission,with lasting consequences across generations,and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.展开更多
Increasing evidences indicate that chronic diseases in offspring may be the result of ancestral environmental exposures. Exposures to environmental compounds in windows of epigenetic susceptibility have been shown to ...Increasing evidences indicate that chronic diseases in offspring may be the result of ancestral environmental exposures. Exposures to environmental compounds in windows of epigenetic susceptibility have been shown to promote epigenetic alterations that can be inherited between generations. DNA methylation, histone modifications, and noncoding RNAs are sound mechanistic candidates for the delivery of environmental information from gametes to zygotes. This review focuses mainly on paternal exposures and assesses the risk of epigenetic alterations in the development of diseases, providing insights into relationships between aberrant sperm epigenetic patterns and offspring health. Elucidation of the mechanisms underlying environmental epigenetic information that survive from epigenetic reprogramming and its transmission to future generations may hold a great promise for providing therapeutic targets for epigenetic diseases associated with environmental exposures.展开更多
Argonaute proteins generally play regulatory roles by forming complexes with the corresponding small RNAs(s RNAs).An expanded Argonaute family with 20 potentially functional members has been identified in Caenorhabdit...Argonaute proteins generally play regulatory roles by forming complexes with the corresponding small RNAs(s RNAs).An expanded Argonaute family with 20 potentially functional members has been identified in Caenorhabditis elegans.Canonical s RNAs in C.elegans are mi RNAs,small interfering RNAs including 22G-RNAs and 26G-RNAs,and 21U-RNAs,which are C.elegans pi RNAs.Previous studies have only covered some of these Argonautes for their s RNA partners,and thus,a systematic study is needed to reveal the comprehensive regulatory networks formed by C.elegans Argonautes and their associated s RNAs.We obtained in situ knockin(KI)strains of all C.elegans Argonautes with fusion tags by CRISPR/Cas9 technology.RNA immunoprecipitation against these endogenously expressed Argonautes and high-throughput sequencing acquired the s RNA profiles of individual Argonautes.The s RNA partners for each Argonaute were then analyzed.We found that there were 10Argonautes enriched mi RNAs,17 Argonautes bound to 22G-RNAs,8 Argonautes bound to 26G-RNAs,and 1 Argonaute PRG-1bound to pi RNAs.Uridylated 22G-RNAs were bound by four Argonautes HRDE-1,WAGO-4,CSR-1,and PPW-2.We found that all four Argonautes played a role in transgenerational epigenetic inheritance.Regulatory roles of the corresponding Argonaute-s RNA complex in managing levels of long transcripts and interspecies regulation were also demonstrated.In this study,we portrayed the s RNAs bound to each functional Argonaute in C.elegans.Bioinformatics analyses together with experimental investigations provided perceptions in the overall view of the regulatory network formed by C.elegans Argonautes and s RNAs.The s RNA profiles bound to individual Argonautes reported here will be valuable resources for further studies.展开更多
基金supported by the National Key R&D Program of China(2017YFA0506400)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)+1 种基金the National Natural Science Foundation of China(31930023,31771333)supported by the China National Postdoctoral Program for Innovative Talents(BX2021356)。
文摘There is accumulating evidence to show that environmental stressors can regulate a variety of phenotypes in descendants through germline-mediated epigenetic inheritance. Studies of model organisms exposed to environmental cues(e.g., diet, heat stress, toxins) indicate that altered DNA methylations, histone modifications, or non-coding RNAs in the germ cells are responsible for the transgenerational effects. In addition,it has also become evident that maternal provision could provide a mechanism for the transgenerational inheritance of stress adaptations that result from ancestral environmental cues. However, how the signal of environmentally-induced stress response transmits from the soma to the germline, which may influence offspring fitness, remains largely elusive. Small RNAs could serve as signaling molecules that transmit between tissues and even across generations. Furthermore, a recent study revealed that neuronal mitochondrial perturbations induce a transgenerational induction of the mitochondrial unfolded protein response mediated by a Wnt-dependent increase in mitochondrial DNA levels. Here, we review recent work on the molecular mechanism by which parental experience can affect future generations and the importance of soma-to-germline signaling for transgenerational inheritance.
基金financially supported by the National Key Research and Development Program of China(grant no.2023YFF1105300).
文摘Consumption of fried foods is highly prevalent in the Western dietary pattern.Western diet has been unfavorably linked with high risk of developing cardiovascular diseases.Heart failure(HF)as a cardiovascular disease subtype is a growing global pandemic with high morbidity and mortality.However,the causal relationship between long-term fried food consumption and incident HF remains unclear.Our population-based study revealed that frequent fried food consumption is strongly associated with 15%higher risk of HF.The causal relationship may be ascribed to the dietary acrylamide exposure in fried foods.Further cross-sectional study evidenced that acrylamide exposure is associated with an increased risk of HF.Furthermore,we discover and demonstrate that chronic acrylamide exposure may induce HF in zebrafish and mice.Mechanistically,we reveal that acrylamide induces energy metabolism disturbance in heart due to the mitochondria dysfunction and metabolic remodeling.Moreover,acrylamide exposure induces myocardial apoptosis via inhibiting NOTCH1-phosphatidylinositol 3-kinase/AKT signaling.In addition,acrylamide exposure could affect heart development during early life stage,and the adverse effect of acrylamide exposure is a threat for next generation via epigenetic change evoked by DNA methyltransferase 1(DNMT1).In this study,we reveal the adverse effects and underlying mechanism of fried foods and acrylamide as a typical food processing contaminant on HF from population-based observations to experimental validation.Collectively,these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered HF and highlight the significance of reducing fried food consumption for lower the risk of HF.
文摘Mental illness remains the greatest chronic health burden globally with few inroads having been made despite significant advances in genomic knowledge in recent decades.The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations,and that has to be supported by a continuous growth in knowledge.The majority of neuropsychiatric symptoms reflect complex geneenvironment interactions,with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms.It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stressrelated behavioural phenotypes in both paternal and maternal lineages,providing further supporting evidence for heritability in humans.However,unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions.While rodents will remain the dominant model system for preclinical studies(especially for addressing complex behavioural phenotypes),there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models.Here,we will discuss the utility and advantages of two alternative model organisms–Caenorhabditis elegans and Drosophila melanogaster-and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.
文摘Background In the current context of global warming,thermal manipulation of avian embryos has received increasing attention as a strategy to promote heat tolerance in avian species by simply increasing the egg incubation temperature.However,because of their likely epigenetic origin,thermal manipulation effects may last more than one generation with consequences for the poultry industry.In this work,a multigenerational and transgenerational analysis of thermal manipulation during embryogenesis was performed to uncover the long-term effects of such procedure.Results Thermal manipulation repeated during 4 generations had an effect on hatchability,body weight,and weight of eggs laid in Japanese quails,with some effects increasing in importance over generations.Moreover,the effects on body weight and egg weight could be transmitted transgenerationally,suggesting non-genetic inheritance mechanisms.This hypothesis is reinforced by the observed reversion of the effect on growth after five unexposed generations.Interestingly,a beneficial effect of thermal manipulation on heat tolerance was observed a few days after hatching,but this effect was not transgenerational.Conclusions Our multigenerational study showed that thermal conditioning of quail embryos has a beneficial effect on post-hatch heat tolerance hampered by transgenerational but reversible defects on growth.Assuming that no genetic variability underlies these changes,this study provides the first demonstration of epigenetic inheritance of traits induced by environmental temperature modification associated with long-term impacts in an avian species.
基金supported by grants from the Guangdong Major Project of Basic and Applied Basic Research(2021B0301030004)the National Natural Science Foundation of China(32488302)+1 种基金the Agricultural Science and Technology Innovation Program(CAAS-ZDRW202404)the China Postdoctoral Science Foundation(2023M733834).
文摘Under the framework of classical genetics and Darwinian theory,DNA sequence variation has long been considered the sole driving force behind the formation of organismal traits.Species passively undergo natural selection through random DNA mutations,gradually adapting to their environments and sustaining their populations(Laland et al.,2014).However,epigenetic studies have revealed that certain traits or phenotypes caused by epigenetic modifications,such as DNA(de)methylation(without any DNA sequence change),can be inherited across generations—a phenomenon termed transgenerational epigenetic inheritance(TEI)(Fitz-James and Cavalli,2022).
基金supported by the National Basic Research Program (973) of China (No. 2007CB948104)the National Natural Science Foundation of China (No. 81070532)the Zhejiang Provincial Natural Science Foundation of China (No. Z207021)
文摘An association between assisted reproductive technology （ART） and neurobehavioral imprinting disorders has been reported in many studies, and it seems that ART may interfere with imprint reprogramming. However, it has never been explored whether epigenetic erros or imprinting disease susceptibility induced by ART can be inherited transgenerationally. Hence, the aim of this study was to determine the effect of in vitro fertilization and embryo transfer （IVF-ET） on transgenerational inheritance in am inbred mouse model. Mice derived from IVF-ET were outcrossed to wild-type C57BL/6J to obtain their female and male line F2 and F3 generations. Their behavior, morphology, histology, and DNA methylation status at several important differentially methylated regions （DMRs） were analyzed by Morris water maze, hematoxylin and eosin （H＆E） staining, and bisulfite genomic sequencing. No significant differences in spatial learning or phenotypic abnormality were found in adults derived from IVF （F1） and female and male line F2 and F3 generations. A borderline trend of hypomethylation was found in H19 DMR CpG island 3 in the female line-derived F3 generation （0.40±0.118, P=0.086）. Methylation status in H19/Igf2 DMR island 1, Igf2 DMR, KvDMR, and Snrpn DMR displayed normal patterns. Methylation percentage did not differ significantly from that of adults conceived naturally, and the expression of the genes they regulated was not disturbed. Transgenerational integrity, such as behavior, morphology, histology, and DNA methylation status, was maintained in these generations, which indicates that exposure of female germ cells to hormonel stimulation and gamete manipulation might not affect the individuals and their descendents.
基金Project No. TKP2021-EGA-20 has been implemented with the support provided by the Ministry of Culture and Innovation of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-EGA funding schemein receipt of a Postdoctoral grant in the frame of the TEPIMEPORY project (Plant Science Project, University of Bordeaux)a Postdoctoral grant of the PRIMA (Partnership for Research and Innovation in the Mediterranean Area) program supported by the European Union in the frame of PROSIT (Plant microbiomes in sustainable viticulture. Grant number 1565)
文摘Plants exhibit remarkable abilities to learn,communicate,memorize,and develop stimulus-dependent decision-making circuits.Unlike animals,plant memory is uniquely rooted in cellular,molecular,and biochemical networks,lacking specialized organs for these functions.Consequently,plants can effectively learn and respond to diverse challenges,becoming used to recurring signals.Artificial intelligence(AI)and machine learning(ML)represent the new frontiers of biological sciences,offering the potential to predict crop behavior under environmental stresses associated with climate change.Epigenetic mechanisms,serving as the foundational blueprints of plant memory,are crucial in regulating plant adaptation to envi-ronmental stimuli.They achieve this adaptation by modulating chromatin structure and acces-sibility,which contribute to gene expression regulation and allow plants to adapt dynam-ically to changing environmental conditions.In this review,we describe novel methods and approaches in AI and ML to elucidate how plant memory occurs in response to environmental stimuli and priming mechanisms.Furthermore,we explore innovative strategies exploiting transgenerational memory for plant breeding to develop crops resilient to multiple stresses.In this context,AI and ML can aid in integrating and analyzing epigenetic data of plant stress responses to optimize the training of the pa-rental plants.
基金supported by grants from the National Key R&D Program of China No.2020YFA0803900(Hui Wang)the National Natural Science Foundation of China No.81973405(Dan Xu),No.82122071(Dan Xu),and No.82030111(Hui Wang)。
文摘The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons.Here we explored how gestational exposure to dexamethasone,a synthetic glucocorticoid commonly used in clinical practice,has lasting effects on offspring's learning and memory.Adult offspring rats of prenatal dexamethasone exposure(PDE)displayed significant impairments in novelty recognition and spatial learning memory,with some phenotypes maintained transgenerationally.PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations,and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory,but these changes failed to carry over to offspring of F5 and F7 generations.Mechanistically,altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission,which might be related to oocyte-specific high expression and transmission of miR-133a-3p.Together,PDE affects hippocampal excitatory synaptic transmission,with lasting consequences across generations,and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.
文摘Increasing evidences indicate that chronic diseases in offspring may be the result of ancestral environmental exposures. Exposures to environmental compounds in windows of epigenetic susceptibility have been shown to promote epigenetic alterations that can be inherited between generations. DNA methylation, histone modifications, and noncoding RNAs are sound mechanistic candidates for the delivery of environmental information from gametes to zygotes. This review focuses mainly on paternal exposures and assesses the risk of epigenetic alterations in the development of diseases, providing insights into relationships between aberrant sperm epigenetic patterns and offspring health. Elucidation of the mechanisms underlying environmental epigenetic information that survive from epigenetic reprogramming and its transmission to future generations may hold a great promise for providing therapeutic targets for epigenetic diseases associated with environmental exposures.
基金supported by the National Key Research and Development Program of China (2019YFA0802600)the National Natural Science Foundation of China (31930019,31900442,32200431)+1 种基金the Strategic Priority Research Program“Biological basis of aging and therapeutic strategies”of the Chinese Academy of Sciences (XDB39010400)the China Postdoctoral Science Foundation (2022M713053)。
文摘Argonaute proteins generally play regulatory roles by forming complexes with the corresponding small RNAs(s RNAs).An expanded Argonaute family with 20 potentially functional members has been identified in Caenorhabditis elegans.Canonical s RNAs in C.elegans are mi RNAs,small interfering RNAs including 22G-RNAs and 26G-RNAs,and 21U-RNAs,which are C.elegans pi RNAs.Previous studies have only covered some of these Argonautes for their s RNA partners,and thus,a systematic study is needed to reveal the comprehensive regulatory networks formed by C.elegans Argonautes and their associated s RNAs.We obtained in situ knockin(KI)strains of all C.elegans Argonautes with fusion tags by CRISPR/Cas9 technology.RNA immunoprecipitation against these endogenously expressed Argonautes and high-throughput sequencing acquired the s RNA profiles of individual Argonautes.The s RNA partners for each Argonaute were then analyzed.We found that there were 10Argonautes enriched mi RNAs,17 Argonautes bound to 22G-RNAs,8 Argonautes bound to 26G-RNAs,and 1 Argonaute PRG-1bound to pi RNAs.Uridylated 22G-RNAs were bound by four Argonautes HRDE-1,WAGO-4,CSR-1,and PPW-2.We found that all four Argonautes played a role in transgenerational epigenetic inheritance.Regulatory roles of the corresponding Argonaute-s RNA complex in managing levels of long transcripts and interspecies regulation were also demonstrated.In this study,we portrayed the s RNAs bound to each functional Argonaute in C.elegans.Bioinformatics analyses together with experimental investigations provided perceptions in the overall view of the regulatory network formed by C.elegans Argonautes and s RNAs.The s RNA profiles bound to individual Argonautes reported here will be valuable resources for further studies.
