Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells ...Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells towards the neuronal state is achieved due to sophisticated mechanisms of epigenetic,transcriptional,and post-transcriptional regulation.Understanding these neurogenic mechanisms is of major importance,not only for shedding light on very complex and crucial developmental processes,but also for the identification of putative reprogramming factors,that harbor hierarchically central regulatory roles in the course of neurogenesis and bare thus the capacity to drive direct reprogramming towards the neuronal fate.The major transcriptional programs that orchestrate the neurogenic process have been the focus of research for many years and key neurogenic transcription factors,as well as repressor complexes,have been identified and employed in direct reprogramming protocols to convert non-neuronal cells,into functional neurons.The post-transcriptional regulation of gene expression during nervous system development has emerged as another important and intricate regulatory layer,strongly contributing to the complexity of the mechanisms controlling neurogenesis and neuronal function.In particular,recent advances are highlighting the importance of specific RNA binding proteins that control major steps of mRNA life cycle during neurogenesis,such as alternative splicing,polyadenylation,stability,and translation.Apart from the RNA binding proteins,microRNAs,a class of small non-coding RNAs that block the translation of their target mRNAs,have also been shown to play crucial roles in all the stages of the neurogenic process,from neural stem/progenitor cell proliferation,neuronal differentiation and migration,to functional maturation.Here,we provide an overview of the most prominent post-transcriptional mechanisms mediated by RNA binding proteins and microRNAs during the neurogenic process,giving particular emphasis on the interplay of specific RNA binding proteins with neurogenic microRNAs.Taking under consideration that the molecular mechanisms of neurogenesis exert high similarity to the ones driving direct neuronal reprogramming,we also discuss the current advances in in vitro and in vivo direct neuronal reprogramming approaches that have employed microRNAs or RNA binding proteins as reprogramming factors,highlighting the so far known mechanisms of their reprogramming action.展开更多
While human immunodeficiency virus 1(HIV-1) infectionis controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from th...While human immunodeficiency virus 1(HIV-1) infectionis controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from the body. Despite decades of research there is still no effective vaccine to prevent HIV-1 infection. Therefore, the possibility of an RNA interference(RNAi)-based cure has become an increasingly explored approach. Endogenous gene expression is controlled at both, transcriptional and post-transcriptional levels by noncoding RNAs, which act through diverse molecular mechanisms including RNAi. RNAi has the potential to control the turning on/off of specific genes through transcriptional gene silencing(TGS), as well as finetuning their expression through post-transcriptional gene silencing(PTGS). In this review we will describe in detail the canonical RNAi pathways for PTGS and TGS, the relationship of TGS with other silencing mechanisms and will discuss a variety of approaches developed to suppress HIV-1 via manipulation of RNAi. We will briefly compare RNAi strategies against other approaches developed to target the virus, highlighting their potential to overcome the major obstacle to finding a cure, which is the specific targeting of the HIV-1 reservoir within latently infected cells.展开更多
RNA-binding proteins(RBPs)are components of the post-transcriptional regulatory system,but their regulatory effects on complex traits remain unknown.Using an integrated strategy involving map-based cloning,functional ...RNA-binding proteins(RBPs)are components of the post-transcriptional regulatory system,but their regulatory effects on complex traits remain unknown.Using an integrated strategy involving map-based cloning,functional characterizations,and transcriptomic and population genomic analyses,we revealed that RBP-K(LOC_Os08g23120),RBP-A(LOC_Os11g41890),and RBP-J(LOC_Os10g33230)encode proteins that form an RBP-A-J-K complex that negatively regulates rice yield-related traits.Examinations of the RBP-A-J-K complex indicated RBP-K functions as a relatively non-specific RBP chaperone that enables RBP-A and RBP-J to function normally.Additionally,RBP-J most likely affects GA pathways,resulting in considerable increases in grain and panicle lengths,but decreases in grain width and thickness.In contrast,RBP-A negatively regulates the expression of genes most likely involved in auxin-regulated pathways controlling cell wall elongation and carbohydrate transport,with substantial effects on the rice grain filling process as well as grain length and weight.Evolutionarily,RBP-K is relatively ancient and highly conserved,whereas RBP-J and RBP-A are more diverse.Thus,the RBP-A-J-K complex may represent a typical functional model for many RBPs and protein complexes that function at transcriptional and post-transcriptional levels in plants and animals for increased functional consistency,efficiency,and versatility,as well as increased evolutionary potential.Our results clearly demonstrate the importance of RBP-mediated post-transcriptional regulation for the diversity of complex traits.Furthermore,rice grain yield and quality may be enhanced by introducing various complete or partial loss-of-function mutations to specific RBP genes using clustered regularly interspaced palindromic repeats(CRISPR)/CRISPR-associated protein 9 technology and by exploiting desirable natural tri-genic allelic combinations at the loci encoding the components of the RBP-A-J-K complex through marker-assisted selection.展开更多
Erythropoiesis is a complex,precise,and lifelong process that is essential for maintaining normal body functions.Its strict regulation is necessary to prevent a variety of blood diseases.Normal erythropoiesis is preci...Erythropoiesis is a complex,precise,and lifelong process that is essential for maintaining normal body functions.Its strict regulation is necessary to prevent a variety of blood diseases.Normal erythropoiesis is precisely regulated by an intricate network that involves transcription levels,signal transduction,and various epigenetic modifications.In recent years,research on posttranscriptional levels in erythropoiesis has expanded significantly.The dynamic regulation of splicing transitions is responsible for changes in protein isoform expression that add new functions beneficial for erythropoiesis.RNA-binding proteins adapt the translation of transcripts to the protein requirements of the cell,yielding mRNA with dynamic translation efficiency.Noncoding RNAs,such as microRNAs and lncRNAs,are indispensable for changing the translational efficiency and/or stability of targeted mRNAs to maintain the normal expression of genes related to erythropoiesis.N6-methyladenosine-dependent regulation of mRNA translation plays an important role in maintaining the expression programs of erythroid-related genes and promoting erythroid lineage determination.This review aims to describe our current understanding of the role of post-transcriptional regulation in erythropoiesis and erythroid-associated diseases,and to shed light on the physiological and pathological implications of the post-transcriptional regulation machinery in erythropoiesis.These may help to further enrich our understanding of the regulatory network of erythropoiesis and provide new strategies for the diagnosis and treatment of erythroid-related diseases.展开更多
MicroRNAs(miRNAs)are a highly conserved class of small(18–24 nucleotides)non-coding RNAs that regulate a broad spectrum of biological processes.Aberrations or corruptions of miRNA functions may lead to deregulated ce...MicroRNAs(miRNAs)are a highly conserved class of small(18–24 nucleotides)non-coding RNAs that regulate a broad spectrum of biological processes.Aberrations or corruptions of miRNA functions may lead to deregulated cell proliferation,tumorigenesis,and ultimately,cancer.Increasing evidences suggested that a large fraction of miRNAs is regulated at the posttranscriptional stage,which impacts on the level and function of miRNAs during cell development and human diseases.Recently,several distinct mechanisms are emerging to regulate the biogenesis,stability and function of miRNAs at post-transcriptional level,such as specific binding to terminal loops of miRNA precursors(primiRNAs or pre-miRNAs)by RNA-binding proteins and 3’-terminal modifications by particular enzymes.Signaling cascades and post-translational modifications of the core components of RNA machinery also take part in the posttranscriptional regulation of miRNAs.展开更多
Functional fullerene derivatives exhibit special inhibitory effects on tumor progress and metastasis via diverse tumor microenvironment regulations,while the elusive molecular mechanisms hinder their clinical transfor...Functional fullerene derivatives exhibit special inhibitory effects on tumor progress and metastasis via diverse tumor microenvironment regulations,while the elusive molecular mechanisms hinder their clinical transformation.Herein,it is initially revealed that nanosize aminated fullerene(C_(70)-EDA)can activate autophagic flux,induce G0/G1 cell cycle arrest to abrogate cancer cell proliferation,and significantly inhibit tumor growth in vivo.Mechanismly,C_(70)-EDA promotes the expression of cathepsin D involved in autophagic activation via post-transcriptional regulation,attributing to the interaction with a panel of RNA binding proteins.The accumulation of cathepsin D induces the autophagic degradation of cyclin D1,which arouses G0/G1 phase arrest.This work unveils the fantastic anti-tumor activity of aminated fullerene,elucidates the molecular mechanism,and provides a new strategy for the antineoplastic drug development on functional fullerenes.展开更多
Flower development plays vital role in horticultural plants.Post-transcriptional regulation via small RNAs is important for plant flower development.To uncover post-transcriptional regulatory networks during the flowe...Flower development plays vital role in horticultural plants.Post-transcriptional regulation via small RNAs is important for plant flower development.To uncover post-transcriptional regulatory networks during the flower development in Dimocarpus longan Lour.‘Shixia’,an economically important fruit crop in subtropical regions,we collected and analyzed sRNA deep-sequencing datasets and degradome libraries Apart from identifying miRNAs and phased siRNA generating loci(PHAS loci),120 hairpin loci,producing abundant sRNAs,were identified by in-house protocols.Our results suggested that 56 miRNA-target pairs,2221-nt-PHAS loci,and 111 hairpin loci are involved in posttranscriptional gene silencing during longan reproductive development.Lineage-specific or species-specific post-transcriptional regulatory modules have been unveiled,including miR482-PHAS and miRN15.miR482-PHAS might be involved in longan flower development beyond their conserved roles in plant defense,and miRN15 is a novel miRNA likely associated with a hairpin locus(HPL-056)to regulate strigolactone receptor gene DWARF14(D14)and the biogenesis of phasiRNAs from D14.These small RNAs are enriched in flower buds,suggesting they are likely involved in post-transcriptional regulatory networks essential for longan flower development via the strigolactone signaling pathway.展开更多
Trans-acting factors controlling mRNA fate are critical for the post-transcriptional regulation of inflammation-related genes, as well as for oncogene and tumor suppressor expression in human cancers. Among them, a gr...Trans-acting factors controlling mRNA fate are critical for the post-transcriptional regulation of inflammation-related genes, as well as for oncogene and tumor suppressor expression in human cancers. Among them, a group of RNA-binding proteins called "Adenylate-Uridylate-rich elements binding proteins"(AUBPs)control mRNA stability or translation through their binding to AU-rich elements enriched in the 3'UTRs of inflammation-and cancer-associated mRNA transcripts. AUBPs play a central role in the recruitment of target mRNAs into small cytoplasmic foci called Processing-bodies and stress granules(also known as P-body/SG). Alterations in the expression and activities of AUBPs and Pbody/SG assembly have been observed to occur with colorectal cancer(CRC)progression, indicating the significant role AUBP-dependent post-transcriptional regulation plays in controlling gene expression during CRC tumorigenesis.Accordingly, these alterations contribute to the pathological expression of many early-response genes involved in prostaglandin biosynthesis and inflammation,along with key oncogenic pathways. In this review, we summarize the current role of these proteins in CRC development. CRC remains a major cause of cancer mortality worldwide and, therefore, targeting these AUBPs to restore efficient post-transcriptional regulation of gene expression may represent an appealing therapeutic strategy.展开更多
Using deep hypothermic circulatory arrest, thoracic aorta diseases and complex heart diseases can be subjected to corrective procedures. However, mechanisms underlying brain protection during deep hypothermic circulat...Using deep hypothermic circulatory arrest, thoracic aorta diseases and complex heart diseases can be subjected to corrective procedures. However, mechanisms underlying brain protection during deep hypothermic circulatory arrest are unclear. After piglet models underwent 60 minutes of deep hypothermic circulatory arrest at 14°C, expression of microRNAs(miRNAs) was analyzed in the hippocampus by microarray. Subsequently, TargetScan 6.2, RNA22 v2.0, miRWalk 2.0, and miRanda were used to predict potential targets, and gene ontology enrichment analysis was carried out to identify functional pathways involved. Quantitative reverse transcription-polymerase chain reaction was conducted to verify miRNA changes. Deep hypothermic circulatory arrest altered the expression of 35 miRNAs. Twenty-two miRNAs were significantly downregulated and thirteen miRNAs were significantly upregulated in the hippocampus after deep hypothermic circulatory arrest. Six out of eight targets among the differentially expressed miRNAs were enriched for neuronal projection(cyclin dependent kinase, CDK16 and SLC1 A2), central nervous system development(FOXO3, TYRO3, and SLC1 A2), ion transmembrane transporter activity(ATP2 B2 and SLC1 A2), and interleukin-6 receptor binding(IL6 R)– these are the key functional pathways involved in cerebral protection during deep hypothermic circulatory arrest. Quantitative reverse transcription-polymerase chain reaction confirmed the results of microarray analysis. Our experimental results illustrate a new role for transcriptional regulation in deep hypothermic circulatory arrest, and provide significant insight for the development of miRNAs to treat brain injuries. All procedures were approved by the Animal Care Committee of Xuanwu Hospital, Capital Medical University, China on March 1, 2017(approval No. XW-INI-AD2017-0112).展开更多
Stress granules(SGs)represent important non-membrane cytoplasmic compartments,involved in cellular adaptation to various stressful conditions(e.g.,hypoxia,nutrient deprivation,oxidative stress).These granules contain ...Stress granules(SGs)represent important non-membrane cytoplasmic compartments,involved in cellular adaptation to various stressful conditions(e.g.,hypoxia,nutrient deprivation,oxidative stress).These granules contain several scaffold proteins and RNA-binding proteins,which bind to mRNAs and keep them translationally silent while protecting them from harmful conditions.Although the role of SGs in cancer development is still poorly known and vary between cancer types,increasing evidence indicate that the expression and/or the activity of several key SGs components are deregulated in colorectal tumors but also in pre-neoplastic conditions(e.g.,inflammatory bowel disease),thus suggesting a potential role in the onset of colorectal cancer(CRC).It is therefore believed that SGs formation importantly contributes to various steps of colorectal tumorigenesis but also in chemoresistance.As CRC is the third most frequent cancer and one of the leading causes of cancer mortality worldwide,development of new therapeutic targets is needed to offset the development of chemoresistance and formation of metastasis.Abolishing SGs assembly may therefore represent an appealing therapeutic strategy to re-sensitize colon cancer cells to anti-cancer chemotherapies.In this review,we summarize the current knowledge on SGs in colorectal cancer and the potential therapeutic strategies that could be employed to target them.展开更多
Ikaros (also known as Lyf-1) was initially described as a lymphoid-specific transcription factor.Although Ikaros has been shown to regulate hematopoietic stem cell renewal,as well as the development and function of ce...Ikaros (also known as Lyf-1) was initially described as a lymphoid-specific transcription factor.Although Ikaros has been shown to regulate hematopoietic stem cell renewal,as well as the development and function of cells from multiple hematopoietic lineages,including the myeloid lineage,Ikaros has primarily been studied in context of lymphoid development and malignancy.This review focuses on the role of Ikaros in myeloid cells.We address the importance of post-transcriptional regulation of Ikaros function;the emerging role of Ikaros in myeloid malignancy;Ikaros as a regulator of myeloid differentiation and function;and the selective expression of Ikaros isoform-x in cells with myeloid potential.We highlight the challenges of dissecting Ikaros function in lineage commitment decisions among lymphoidmyeloid progenitors that have emerged as a major myeloid differentiation pathway in recent studies,which leads to reconstruction of the traditional map of murine and human hematopoiesis.展开更多
Xenopus ZFP36L1(zinc finger protein 36,C3H type-like 1)belongs to the ZFP36 family of RNA-binding proteins,which contains two characteristic tandem CCCH-type zinc-finger domains.The ZFP36 proteins can bind AU-rich ele...Xenopus ZFP36L1(zinc finger protein 36,C3H type-like 1)belongs to the ZFP36 family of RNA-binding proteins,which contains two characteristic tandem CCCH-type zinc-finger domains.The ZFP36 proteins can bind AU-rich elements in 3'untranslated regions of target mRNAs and promote their turnover.However,the expression and role of ZFP36 genes during neural development in Xenopus embryos remains largely unknown.The present study showed that Xenopus ZFP36L1 was expressed at the dorsal part of the forebrain,forebrain-midbrain boundary,and midbrain-hindbrain boundary from late neurula stages to tadpole stages of embryonic development.Overexpression of XZFP36L1 in Xenopus embryos inhibited neural induction and differentiation,leading to severe neural tube defects.The function of XZP36L1 requires both its zinc finger and C terminal domains,which also affect its subcellular localization.These results suggest that XZFP36L1 is likely involved in neural development in Xenopus and might play an important role in post-transcriptional regulation.展开更多
As nucleic acid-guided endonucleases,some prokaryotic Argonautes have been used as programmable nucleases.Natronobacterium gregoryi Argonaute(NgAgo)has also been proposed for gene editing,but this remains very controv...As nucleic acid-guided endonucleases,some prokaryotic Argonautes have been used as programmable nucleases.Natronobacterium gregoryi Argonaute(NgAgo)has also been proposed for gene editing,but this remains very controversial.Until now,the endogenous nucleic acids that bind to NgAgo in Natronobacterium gregoryi sp2(N.gregoryi sp2)have not been characterized.We expressed the conserved PIWI domain of NgAgo and used it to induce anti-PIWI antibody.We also cultured the N.gregoryi sp2 strain and performed immunoprecipitation,chromatin immunoprecipitation(ChIP),and RNA immunoprecipitation(RIP)assays.The nucleic acids that endogenously bound NgAgo in N.gregoryi sp2 cells were sequenced and analyzed.The results showed that NgAgo endogenously bound RNA rather than DNA.NgAgo-associated RNAs were mainly transcripts of genes that encoded tRNA,transcriptional regulators,RNA polymerases,and RNA-binding proteins.NgAgo mainly binds to the transcripts inside genes or in their upstream sequences.Interestingly,the top enriched motif of peaks was the same as that of miR-1289,suggesting that NgAgo may regulate gene expression post-transcriptionally.GO enrichment analysis showed that the peak-associated genes were enriched in transmembrane transport processes.These results revealed that NgAgo binds RNA and may function in post-transcriptional regulation in vivo.展开更多
The induction of genes encoded in the open reading frames (ORFs) of chloroplast genomes have been posited to be influenced by ambient light condition. The current study focused on determining which of the six ORFs, en...The induction of genes encoded in the open reading frames (ORFs) of chloroplast genomes have been posited to be influenced by ambient light condition. The current study focused on determining which of the six ORFs, encoding the genes ycf 1, ycf 2, psbD (photosystem II), rbcl (Rubisco), matK (Maturase K) and rpoC1 (RNA polymerase) were influenced by light. Characterization of gene expression at the whole plant level and callus stage facilitates the identification of transcripts which are differentially regulated under these environmental conditions. Specificity of these primers was tested against genomic DNA and total RNA. Transcripts of six targeted genes were detected in all three replicates of the green and white callus under light and dark conditions, except for ycf 2 gene in green callus under light. The result showed that a partial transcript of the gene ycf 2 located on the J. curcas chloroplast genome was not detectable using reverse transcription PCR. This finding was then validated using quantitative real-time PCR. The gene was suspected to be post-transcriptionally modified. The transcripts of the remaining five ORFs could be detected using quantitative real-time PCR. Specific transcripts can be identified for application as biomarkers for selection of callus for plantlet regeneration.展开更多
Coronavirus disease 2019(COVID-19)has impacted almost every part of human lifeworldwide,posing amassive threat to human health.The lack of time for new drug discovery and the urgent need for rapid disease control to r...Coronavirus disease 2019(COVID-19)has impacted almost every part of human lifeworldwide,posing amassive threat to human health.The lack of time for new drug discovery and the urgent need for rapid disease control to reduce mortality have led to a search for quick and effective alternatives to novel therapeutics,for example drug repurposing.To identify potentially repurposable drugs,we employed a systematic approach to mine candidates from U.S.FDA-approved drugs and preclinical small-molecule compounds by integrating gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from patients withmild and severe COVID-19(GEO:GSE145926,public data available and accessed on 22 April 2020).We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19.We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a,two chemical inhibitors of glycosylation(a post-translational modification)on the replication of the single-stranded ribonucleic acid(ssRNA)virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators(IFNs and ISGs).In conclusion,we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach,which may have the potential for treating these viral infections and their complications(sepsis).展开更多
Theopen reading regions of ZmPHT1s(inorganic phosphate[Pij transporters)inmaize possess target sites of microRNA399(miR399).However,the relationship between miR399 and ZmPHT1s and its functional importance in response...Theopen reading regions of ZmPHT1s(inorganic phosphate[Pij transporters)inmaize possess target sites of microRNA399(miR399).However,the relationship between miR399 and ZmPHT1s and its functional importance in response to Pi deficiency remain to be explored.We show here that ZmPHT1;1,ZmPHT1;3,and ZmPHT1;13 are the targets of ZmmiRNA399.We found that a long non-coding RNA,PILNCR2(Pi-deficiency-induced IncRNA 2),is transcribed from the opposing DNA strand of ZmPHT1;1 and predominantly localized in the cytoplasm.A ribonuclease protection assay and an RNA-RNA binding assay showed that PILNCR2 and ZmPHT1s could form the RNA/RNA duplexes in vivo and in vitro.A co-expression assay in N.benthamiana revealed that the PILNCR2/ZmPHT1 RNA/RNA duplexes interfere with miR399-guided cleavage of ZmPHT1 mRNAs.Overexpression of PILNCR2 increased low-Pi tolerance in maize,whereas its knockout and knockdown decreased low-Pi tolerance in maize.Consistently,ZmPHT1;3 and ZmPHT1;13 mRNA abundance was increased in transgenic plants overexpressing PILNCR2 but reduced in its knock-out mutants,suggesting that PILNCR2 positively regulates the mRNA abundance of ZmPHT1;3 and ZmPHT1;13 in maize.Collectively,these results indicate that PILNCR2 plays an important role in maize Pihomeostasisby interfering with miRNA399-guided cleavageof ZmPHT1mRNAs.展开更多
After implantation,complex and highly specialized molecular events render functionally distinct organ formation,whereas how the epigenome shapes organ-specific development remains to be fully elucidated.Here,nano-hmC-...After implantation,complex and highly specialized molecular events render functionally distinct organ formation,whereas how the epigenome shapes organ-specific development remains to be fully elucidated.Here,nano-hmC-Seal,RNA bisulfite sequencing(RNA-BisSeq),and RNA sequencing(RNA-Seq)were performed,and the first multilayer landscapes of DNA 5-hydroxymethylcytosine(5hmC)and RNA 5-methylcytosine(m^(5)C)epigenomes were obtained in the heart,kidney,liver,and lung of the human foetuses at 13-28 weeks with 123 samples in total.We identified 70,091 and 503 organ-and stage-specific differentially hydroxymethylated regions(DhMRs)and m^(5)C-modified mRNAs,respectively.The key transcription factors(TFs),T-box transcription factor 20(TBX20),paired box 8(PAX8),krueppel-like factor 1(KLF1),transcription factor 21(TCF21),and CCAAT enhancer binding protein beta(CEBPB),specifically contribute to the formation of distinct organs at different stages.Additionally,5hmC-enriched Alu elements may participate in the regulation of expression of TF-targeted genes.Our integrated studies reveal a putative essential link between DNA modification and RNA methylation,and illustrate the epigenetic maps during human foetal organogenesis,which provide a foundation for an in-depth understanding of the epigenetic mechanisms underlying early development and birth defects.展开更多
Germinal centers(GCs)are essential for the establishment of long-lasting antibody responses.GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into funct...Germinal centers(GCs)are essential for the establishment of long-lasting antibody responses.GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell proteome.However,the critical proteins driving these key mechanisms are still unknown.Here,we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses.TIA1-and TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection,expansion and differentiation into B-cell clones producing high-affinity antibodies.Mechanistically,TIA1 and TIAL1 control the transcriptional identity of dark-and light-zone GC B cells and enable timely expression of the prosurvival molecule MCL1.Thus,we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.展开更多
Chloroplasts evolved from an ancient cyanobacterial endosymbiont more than 1.5 billion years ago.During subsequent coevolution with the nuclear genome,the chloroplast genome has remained independent,albeit strongly re...Chloroplasts evolved from an ancient cyanobacterial endosymbiont more than 1.5 billion years ago.During subsequent coevolution with the nuclear genome,the chloroplast genome has remained independent,albeit strongly reduced,with its own transcriptional machinery and distinct features,such as chloroplast-specific innovations in gene expression and complicated post-transcriptional processing.Light activates the expression of chloroplast genes via mechanisms that optimize photosynthesis,minimize photodamage,and prioritize energy investments.Over the past few years,studies have moved from describing phases of chloroplast gene expression to exploring the underlying mechanisms.In this review,we focus on recent advances and emerging principles that govern chloroplast gene expression in land plants.We discuss engineering of pentatricopeptide repeat proteins and its biotechnological effects on chloroplast RNA research;new techniques for characterizing the molecular mechanisms of chloroplast gene expression;and important aspects of chloroplast gene expression for improving crop yield and stress tolerance.We also discuss biological and mechanistic questions that remain to be answered in the future.展开更多
基金supported by Stavros Niarhos FoundationGreek‘Flagship Action for the Study of Neurodegenerative Diseases on the Basis of Precision Medicine’(to DT).
文摘Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells towards the neuronal state is achieved due to sophisticated mechanisms of epigenetic,transcriptional,and post-transcriptional regulation.Understanding these neurogenic mechanisms is of major importance,not only for shedding light on very complex and crucial developmental processes,but also for the identification of putative reprogramming factors,that harbor hierarchically central regulatory roles in the course of neurogenesis and bare thus the capacity to drive direct reprogramming towards the neuronal fate.The major transcriptional programs that orchestrate the neurogenic process have been the focus of research for many years and key neurogenic transcription factors,as well as repressor complexes,have been identified and employed in direct reprogramming protocols to convert non-neuronal cells,into functional neurons.The post-transcriptional regulation of gene expression during nervous system development has emerged as another important and intricate regulatory layer,strongly contributing to the complexity of the mechanisms controlling neurogenesis and neuronal function.In particular,recent advances are highlighting the importance of specific RNA binding proteins that control major steps of mRNA life cycle during neurogenesis,such as alternative splicing,polyadenylation,stability,and translation.Apart from the RNA binding proteins,microRNAs,a class of small non-coding RNAs that block the translation of their target mRNAs,have also been shown to play crucial roles in all the stages of the neurogenic process,from neural stem/progenitor cell proliferation,neuronal differentiation and migration,to functional maturation.Here,we provide an overview of the most prominent post-transcriptional mechanisms mediated by RNA binding proteins and microRNAs during the neurogenic process,giving particular emphasis on the interplay of specific RNA binding proteins with neurogenic microRNAs.Taking under consideration that the molecular mechanisms of neurogenesis exert high similarity to the ones driving direct neuronal reprogramming,we also discuss the current advances in in vitro and in vivo direct neuronal reprogramming approaches that have employed microRNAs or RNA binding proteins as reprogramming factors,highlighting the so far known mechanisms of their reprogramming action.
文摘While human immunodeficiency virus 1(HIV-1) infectionis controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from the body. Despite decades of research there is still no effective vaccine to prevent HIV-1 infection. Therefore, the possibility of an RNA interference(RNAi)-based cure has become an increasingly explored approach. Endogenous gene expression is controlled at both, transcriptional and post-transcriptional levels by noncoding RNAs, which act through diverse molecular mechanisms including RNAi. RNAi has the potential to control the turning on/off of specific genes through transcriptional gene silencing(TGS), as well as finetuning their expression through post-transcriptional gene silencing(PTGS). In this review we will describe in detail the canonical RNAi pathways for PTGS and TGS, the relationship of TGS with other silencing mechanisms and will discuss a variety of approaches developed to suppress HIV-1 via manipulation of RNAi. We will briefly compare RNAi strategies against other approaches developed to target the virus, highlighting their potential to overcome the major obstacle to finding a cure, which is the specific targeting of the HIV-1 reservoir within latently infected cells.
基金supported by the Innovation Program of Shanghai Municipal Education Commission(2023ZKZD05)the National Natural Science Foundation of China(32172043,31971918 and 32170356)+2 种基金the Shanghai Science and Technology Innovation Action Plan Project(22N11900200)the Innovation Program of Chinese Academy of Agricultural Sciencesthe grant from the National Key Research and Development Program of China(2021YFA1300401).
文摘RNA-binding proteins(RBPs)are components of the post-transcriptional regulatory system,but their regulatory effects on complex traits remain unknown.Using an integrated strategy involving map-based cloning,functional characterizations,and transcriptomic and population genomic analyses,we revealed that RBP-K(LOC_Os08g23120),RBP-A(LOC_Os11g41890),and RBP-J(LOC_Os10g33230)encode proteins that form an RBP-A-J-K complex that negatively regulates rice yield-related traits.Examinations of the RBP-A-J-K complex indicated RBP-K functions as a relatively non-specific RBP chaperone that enables RBP-A and RBP-J to function normally.Additionally,RBP-J most likely affects GA pathways,resulting in considerable increases in grain and panicle lengths,but decreases in grain width and thickness.In contrast,RBP-A negatively regulates the expression of genes most likely involved in auxin-regulated pathways controlling cell wall elongation and carbohydrate transport,with substantial effects on the rice grain filling process as well as grain length and weight.Evolutionarily,RBP-K is relatively ancient and highly conserved,whereas RBP-J and RBP-A are more diverse.Thus,the RBP-A-J-K complex may represent a typical functional model for many RBPs and protein complexes that function at transcriptional and post-transcriptional levels in plants and animals for increased functional consistency,efficiency,and versatility,as well as increased evolutionary potential.Our results clearly demonstrate the importance of RBP-mediated post-transcriptional regulation for the diversity of complex traits.Furthermore,rice grain yield and quality may be enhanced by introducing various complete or partial loss-of-function mutations to specific RBP genes using clustered regularly interspaced palindromic repeats(CRISPR)/CRISPR-associated protein 9 technology and by exploiting desirable natural tri-genic allelic combinations at the loci encoding the components of the RBP-A-J-K complex through marker-assisted selection.
基金supported by grants from the National Natural Science Foundation of China(Grant numbers 81920108004 and 82270127)the Fundamental Research Funds of the Central Universities of Central South University(Grant number 2021zzts0562)the Fundamental Research Funds for the Scientific Research Innovation Project of Hunan Province(Grant number CX20210182).
文摘Erythropoiesis is a complex,precise,and lifelong process that is essential for maintaining normal body functions.Its strict regulation is necessary to prevent a variety of blood diseases.Normal erythropoiesis is precisely regulated by an intricate network that involves transcription levels,signal transduction,and various epigenetic modifications.In recent years,research on posttranscriptional levels in erythropoiesis has expanded significantly.The dynamic regulation of splicing transitions is responsible for changes in protein isoform expression that add new functions beneficial for erythropoiesis.RNA-binding proteins adapt the translation of transcripts to the protein requirements of the cell,yielding mRNA with dynamic translation efficiency.Noncoding RNAs,such as microRNAs and lncRNAs,are indispensable for changing the translational efficiency and/or stability of targeted mRNAs to maintain the normal expression of genes related to erythropoiesis.N6-methyladenosine-dependent regulation of mRNA translation plays an important role in maintaining the expression programs of erythroid-related genes and promoting erythroid lineage determination.This review aims to describe our current understanding of the role of post-transcriptional regulation in erythropoiesis and erythroid-associated diseases,and to shed light on the physiological and pathological implications of the post-transcriptional regulation machinery in erythropoiesis.These may help to further enrich our understanding of the regulatory network of erythropoiesis and provide new strategies for the diagnosis and treatment of erythroid-related diseases.
基金This work was supported by National Natural Science Foundation of China (Grant Noa. 30930009) and Science and Technology Planning Project of Guangdong Province, China (Grant Nos, 2011A020201008).
文摘MicroRNAs(miRNAs)are a highly conserved class of small(18–24 nucleotides)non-coding RNAs that regulate a broad spectrum of biological processes.Aberrations or corruptions of miRNA functions may lead to deregulated cell proliferation,tumorigenesis,and ultimately,cancer.Increasing evidences suggested that a large fraction of miRNAs is regulated at the posttranscriptional stage,which impacts on the level and function of miRNAs during cell development and human diseases.Recently,several distinct mechanisms are emerging to regulate the biogenesis,stability and function of miRNAs at post-transcriptional level,such as specific binding to terminal loops of miRNA precursors(primiRNAs or pre-miRNAs)by RNA-binding proteins and 3’-terminal modifications by particular enzymes.Signaling cascades and post-translational modifications of the core components of RNA machinery also take part in the posttranscriptional regulation of miRNAs.
基金This work was supported by the National Natural Science Foundation of China(No.51802310)All animal experiments were conducted according to protocols approved by the Institutional Animal Care and Use Committee in the Institute of Chemistry,Chinese Academy of Sciences.
文摘Functional fullerene derivatives exhibit special inhibitory effects on tumor progress and metastasis via diverse tumor microenvironment regulations,while the elusive molecular mechanisms hinder their clinical transformation.Herein,it is initially revealed that nanosize aminated fullerene(C_(70)-EDA)can activate autophagic flux,induce G0/G1 cell cycle arrest to abrogate cancer cell proliferation,and significantly inhibit tumor growth in vivo.Mechanismly,C_(70)-EDA promotes the expression of cathepsin D involved in autophagic activation via post-transcriptional regulation,attributing to the interaction with a panel of RNA binding proteins.The accumulation of cathepsin D induces the autophagic degradation of cyclin D1,which arouses G0/G1 phase arrest.This work unveils the fantastic anti-tumor activity of aminated fullerene,elucidates the molecular mechanism,and provides a new strategy for the antineoplastic drug development on functional fullerenes.
基金funded by the National Key Research and Developmental Program of China(Grant No.2018YFD1000104)supported by awards from the National Natural Science Foundation of China(Grant Nos.32002009 and 32072547)The Special Support Program of Guangdong Province(Grant No.2019TX05N193).
文摘Flower development plays vital role in horticultural plants.Post-transcriptional regulation via small RNAs is important for plant flower development.To uncover post-transcriptional regulatory networks during the flower development in Dimocarpus longan Lour.‘Shixia’,an economically important fruit crop in subtropical regions,we collected and analyzed sRNA deep-sequencing datasets and degradome libraries Apart from identifying miRNAs and phased siRNA generating loci(PHAS loci),120 hairpin loci,producing abundant sRNAs,were identified by in-house protocols.Our results suggested that 56 miRNA-target pairs,2221-nt-PHAS loci,and 111 hairpin loci are involved in posttranscriptional gene silencing during longan reproductive development.Lineage-specific or species-specific post-transcriptional regulatory modules have been unveiled,including miR482-PHAS and miRN15.miR482-PHAS might be involved in longan flower development beyond their conserved roles in plant defense,and miRN15 is a novel miRNA likely associated with a hairpin locus(HPL-056)to regulate strigolactone receptor gene DWARF14(D14)and the biogenesis of phasiRNAs from D14.These small RNAs are enriched in flower buds,suggesting they are likely involved in post-transcriptional regulatory networks essential for longan flower development via the strigolactone signaling pathway.
基金Supported by the National Institutes of Health/National Cancer Institute Cancer Center Support grant P30 CA168524(DD)supported by a grant of the Geneva Cancer League(Grant no.1711)
文摘Trans-acting factors controlling mRNA fate are critical for the post-transcriptional regulation of inflammation-related genes, as well as for oncogene and tumor suppressor expression in human cancers. Among them, a group of RNA-binding proteins called "Adenylate-Uridylate-rich elements binding proteins"(AUBPs)control mRNA stability or translation through their binding to AU-rich elements enriched in the 3'UTRs of inflammation-and cancer-associated mRNA transcripts. AUBPs play a central role in the recruitment of target mRNAs into small cytoplasmic foci called Processing-bodies and stress granules(also known as P-body/SG). Alterations in the expression and activities of AUBPs and Pbody/SG assembly have been observed to occur with colorectal cancer(CRC)progression, indicating the significant role AUBP-dependent post-transcriptional regulation plays in controlling gene expression during CRC tumorigenesis.Accordingly, these alterations contribute to the pathological expression of many early-response genes involved in prostaglandin biosynthesis and inflammation,along with key oncogenic pathways. In this review, we summarize the current role of these proteins in CRC development. CRC remains a major cause of cancer mortality worldwide and, therefore, targeting these AUBPs to restore efficient post-transcriptional regulation of gene expression may represent an appealing therapeutic strategy.
基金supported by the National Natural Science Foundation of China,No.81401084(to XHW)the Beijing Municipal Administration of Hospital Ascent Plan in China,No.DFL20150802(to TLW)+2 种基金the Beijing 215 High Level Healthcare Talent Plan Academic Leader in China,No.008-0027(to TLW)the Beijing Municipal Commission of Health and Family Planning in China,No.PXM2017_026283_000002(to TLW)the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support in China,No.ZYLX201706(to TLW),303-01-005-0137-11(to TLW),65683.00(to TLW)
文摘Using deep hypothermic circulatory arrest, thoracic aorta diseases and complex heart diseases can be subjected to corrective procedures. However, mechanisms underlying brain protection during deep hypothermic circulatory arrest are unclear. After piglet models underwent 60 minutes of deep hypothermic circulatory arrest at 14°C, expression of microRNAs(miRNAs) was analyzed in the hippocampus by microarray. Subsequently, TargetScan 6.2, RNA22 v2.0, miRWalk 2.0, and miRanda were used to predict potential targets, and gene ontology enrichment analysis was carried out to identify functional pathways involved. Quantitative reverse transcription-polymerase chain reaction was conducted to verify miRNA changes. Deep hypothermic circulatory arrest altered the expression of 35 miRNAs. Twenty-two miRNAs were significantly downregulated and thirteen miRNAs were significantly upregulated in the hippocampus after deep hypothermic circulatory arrest. Six out of eight targets among the differentially expressed miRNAs were enriched for neuronal projection(cyclin dependent kinase, CDK16 and SLC1 A2), central nervous system development(FOXO3, TYRO3, and SLC1 A2), ion transmembrane transporter activity(ATP2 B2 and SLC1 A2), and interleukin-6 receptor binding(IL6 R)– these are the key functional pathways involved in cerebral protection during deep hypothermic circulatory arrest. Quantitative reverse transcription-polymerase chain reaction confirmed the results of microarray analysis. Our experimental results illustrate a new role for transcriptional regulation in deep hypothermic circulatory arrest, and provide significant insight for the development of miRNAs to treat brain injuries. All procedures were approved by the Animal Care Committee of Xuanwu Hospital, Capital Medical University, China on March 1, 2017(approval No. XW-INI-AD2017-0112).
基金Supported by Geneva Cancer League,No.1711National Institutes of Health,No.R01 CA243445and National Cancer Institute Cancer Center Support Grant,No.P30 CA168524.
文摘Stress granules(SGs)represent important non-membrane cytoplasmic compartments,involved in cellular adaptation to various stressful conditions(e.g.,hypoxia,nutrient deprivation,oxidative stress).These granules contain several scaffold proteins and RNA-binding proteins,which bind to mRNAs and keep them translationally silent while protecting them from harmful conditions.Although the role of SGs in cancer development is still poorly known and vary between cancer types,increasing evidence indicate that the expression and/or the activity of several key SGs components are deregulated in colorectal tumors but also in pre-neoplastic conditions(e.g.,inflammatory bowel disease),thus suggesting a potential role in the onset of colorectal cancer(CRC).It is therefore believed that SGs formation importantly contributes to various steps of colorectal tumorigenesis but also in chemoresistance.As CRC is the third most frequent cancer and one of the leading causes of cancer mortality worldwide,development of new therapeutic targets is needed to offset the development of chemoresistance and formation of metastasis.Abolishing SGs assembly may therefore represent an appealing therapeutic strategy to re-sensitize colon cancer cells to anti-cancer chemotherapies.In this review,we summarize the current knowledge on SGs in colorectal cancer and the potential therapeutic strategies that could be employed to target them.
文摘Ikaros (also known as Lyf-1) was initially described as a lymphoid-specific transcription factor.Although Ikaros has been shown to regulate hematopoietic stem cell renewal,as well as the development and function of cells from multiple hematopoietic lineages,including the myeloid lineage,Ikaros has primarily been studied in context of lymphoid development and malignancy.This review focuses on the role of Ikaros in myeloid cells.We address the importance of post-transcriptional regulation of Ikaros function;the emerging role of Ikaros in myeloid malignancy;Ikaros as a regulator of myeloid differentiation and function;and the selective expression of Ikaros isoform-x in cells with myeloid potential.We highlight the challenges of dissecting Ikaros function in lineage commitment decisions among lymphoidmyeloid progenitors that have emerged as a major myeloid differentiation pathway in recent studies,which leads to reconstruction of the traditional map of murine and human hematopoiesis.
基金National Natural Science Foundation of China(90919039,C120106)the National Institute for Basic Biology,Japan,for the Xl073b24 clone.
文摘Xenopus ZFP36L1(zinc finger protein 36,C3H type-like 1)belongs to the ZFP36 family of RNA-binding proteins,which contains two characteristic tandem CCCH-type zinc-finger domains.The ZFP36 proteins can bind AU-rich elements in 3'untranslated regions of target mRNAs and promote their turnover.However,the expression and role of ZFP36 genes during neural development in Xenopus embryos remains largely unknown.The present study showed that Xenopus ZFP36L1 was expressed at the dorsal part of the forebrain,forebrain-midbrain boundary,and midbrain-hindbrain boundary from late neurula stages to tadpole stages of embryonic development.Overexpression of XZFP36L1 in Xenopus embryos inhibited neural induction and differentiation,leading to severe neural tube defects.The function of XZP36L1 requires both its zinc finger and C terminal domains,which also affect its subcellular localization.These results suggest that XZFP36L1 is likely involved in neural development in Xenopus and might play an important role in post-transcriptional regulation.
基金The datasets generated during the current study are available in the Sequence Read Archive(SRA)repository under the accession number PRJNA720376(BioProject)GenBank under the accession number PKKI00000000.
文摘As nucleic acid-guided endonucleases,some prokaryotic Argonautes have been used as programmable nucleases.Natronobacterium gregoryi Argonaute(NgAgo)has also been proposed for gene editing,but this remains very controversial.Until now,the endogenous nucleic acids that bind to NgAgo in Natronobacterium gregoryi sp2(N.gregoryi sp2)have not been characterized.We expressed the conserved PIWI domain of NgAgo and used it to induce anti-PIWI antibody.We also cultured the N.gregoryi sp2 strain and performed immunoprecipitation,chromatin immunoprecipitation(ChIP),and RNA immunoprecipitation(RIP)assays.The nucleic acids that endogenously bound NgAgo in N.gregoryi sp2 cells were sequenced and analyzed.The results showed that NgAgo endogenously bound RNA rather than DNA.NgAgo-associated RNAs were mainly transcripts of genes that encoded tRNA,transcriptional regulators,RNA polymerases,and RNA-binding proteins.NgAgo mainly binds to the transcripts inside genes or in their upstream sequences.Interestingly,the top enriched motif of peaks was the same as that of miR-1289,suggesting that NgAgo may regulate gene expression post-transcriptionally.GO enrichment analysis showed that the peak-associated genes were enriched in transmembrane transport processes.These results revealed that NgAgo binds RNA and may function in post-transcriptional regulation in vivo.
文摘The induction of genes encoded in the open reading frames (ORFs) of chloroplast genomes have been posited to be influenced by ambient light condition. The current study focused on determining which of the six ORFs, encoding the genes ycf 1, ycf 2, psbD (photosystem II), rbcl (Rubisco), matK (Maturase K) and rpoC1 (RNA polymerase) were influenced by light. Characterization of gene expression at the whole plant level and callus stage facilitates the identification of transcripts which are differentially regulated under these environmental conditions. Specificity of these primers was tested against genomic DNA and total RNA. Transcripts of six targeted genes were detected in all three replicates of the green and white callus under light and dark conditions, except for ycf 2 gene in green callus under light. The result showed that a partial transcript of the gene ycf 2 located on the J. curcas chloroplast genome was not detectable using reverse transcription PCR. This finding was then validated using quantitative real-time PCR. The gene was suspected to be post-transcriptionally modified. The transcripts of the remaining five ORFs could be detected using quantitative real-time PCR. Specific transcripts can be identified for application as biomarkers for selection of callus for plantlet regeneration.
基金The work was partially supported by the National Institutes of Health(NIH,grants No.P20GM113123 to J.H.,R01AI138203 and AI109317 to M.W.)the Science and Technology Department of Sichuan Province(grant No.2019YJ0050)to C.LThe funders of the study had no role in study design,data collection,data analysis,data interpretation,or writing of the paper.Influenza A virus(IAV,Puerto Rico/8/1934(H1N1))viral stocks were provided by the laboratory of Dr.NadeemKhan(University of North Dakota).Figure 1 was created by modifying illustrations provided by Servier Medical Art(SMART)licensed under a Creative Commons Attribution 3.0 Unported License(smart.servier.com)and Vecteezy.com.
文摘Coronavirus disease 2019(COVID-19)has impacted almost every part of human lifeworldwide,posing amassive threat to human health.The lack of time for new drug discovery and the urgent need for rapid disease control to reduce mortality have led to a search for quick and effective alternatives to novel therapeutics,for example drug repurposing.To identify potentially repurposable drugs,we employed a systematic approach to mine candidates from U.S.FDA-approved drugs and preclinical small-molecule compounds by integrating gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from patients withmild and severe COVID-19(GEO:GSE145926,public data available and accessed on 22 April 2020).We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19.We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a,two chemical inhibitors of glycosylation(a post-translational modification)on the replication of the single-stranded ribonucleic acid(ssRNA)virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators(IFNs and ISGs).In conclusion,we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach,which may have the potential for treating these viral infections and their complications(sepsis).
基金the National Key Research and Development Program of China(2021YFF1000500)the Agricultural Science and Technology Innovation Program of CAAS to W.-X.L.
文摘Theopen reading regions of ZmPHT1s(inorganic phosphate[Pij transporters)inmaize possess target sites of microRNA399(miR399).However,the relationship between miR399 and ZmPHT1s and its functional importance in response to Pi deficiency remain to be explored.We show here that ZmPHT1;1,ZmPHT1;3,and ZmPHT1;13 are the targets of ZmmiRNA399.We found that a long non-coding RNA,PILNCR2(Pi-deficiency-induced IncRNA 2),is transcribed from the opposing DNA strand of ZmPHT1;1 and predominantly localized in the cytoplasm.A ribonuclease protection assay and an RNA-RNA binding assay showed that PILNCR2 and ZmPHT1s could form the RNA/RNA duplexes in vivo and in vitro.A co-expression assay in N.benthamiana revealed that the PILNCR2/ZmPHT1 RNA/RNA duplexes interfere with miR399-guided cleavage of ZmPHT1 mRNAs.Overexpression of PILNCR2 increased low-Pi tolerance in maize,whereas its knockout and knockdown decreased low-Pi tolerance in maize.Consistently,ZmPHT1;3 and ZmPHT1;13 mRNA abundance was increased in transgenic plants overexpressing PILNCR2 but reduced in its knock-out mutants,suggesting that PILNCR2 positively regulates the mRNA abundance of ZmPHT1;3 and ZmPHT1;13 in maize.Collectively,these results indicate that PILNCR2 plays an important role in maize Pihomeostasisby interfering with miRNA399-guided cleavageof ZmPHT1mRNAs.
基金supported by the National Key R&D Program of China(Grant Nos.2019YFA0110900,2019YFA0802202,2019YFA0802200 and 2020YFA0803401)the National Natural Science Foundation of China(Grant Nos.31870817 and 32170819)+2 种基金the Scientific and Technological Innovation Talent Project of Universities of Henan Province,China(Grant No.20HASTIT045)the Shanghai Municipal Science and Technology Major Project,China(Grant No.2017SHZDZX01)the China Postdoctoral Science Foundation(Grant No.2021M692927).
文摘After implantation,complex and highly specialized molecular events render functionally distinct organ formation,whereas how the epigenome shapes organ-specific development remains to be fully elucidated.Here,nano-hmC-Seal,RNA bisulfite sequencing(RNA-BisSeq),and RNA sequencing(RNA-Seq)were performed,and the first multilayer landscapes of DNA 5-hydroxymethylcytosine(5hmC)and RNA 5-methylcytosine(m^(5)C)epigenomes were obtained in the heart,kidney,liver,and lung of the human foetuses at 13-28 weeks with 123 samples in total.We identified 70,091 and 503 organ-and stage-specific differentially hydroxymethylated regions(DhMRs)and m^(5)C-modified mRNAs,respectively.The key transcription factors(TFs),T-box transcription factor 20(TBX20),paired box 8(PAX8),krueppel-like factor 1(KLF1),transcription factor 21(TCF21),and CCAAT enhancer binding protein beta(CEBPB),specifically contribute to the formation of distinct organs at different stages.Additionally,5hmC-enriched Alu elements may participate in the regulation of expression of TF-targeted genes.Our integrated studies reveal a putative essential link between DNA modification and RNA methylation,and illustrate the epigenetic maps during human foetal organogenesis,which provide a foundation for an in-depth understanding of the epigenetic mechanisms underlying early development and birth defects.
基金We thank all personnel from the Toulouse animal facility CREFRE and from the flow cytometry,imaging,transcriptomics and bioinformatics technical platforms of INFINITy.M.D.D-M.is supported by ATIP-Avenir-Plan Cancer(C18003BS),ANR(ANR-20-CE15-0007)foundation ARSEP R19201BB,foundation ARC,La Ligue Contre Le Cancer and INSPIRE(Region Occitanie,Inserm and CHU Toulouse)M.T.is supported with a BBSRC core funding grant and a Wellcome Investigator award(200823/Z/16/Z).D.C.-S.is supported by Boehringer Ingelheim Fonds.
文摘Germinal centers(GCs)are essential for the establishment of long-lasting antibody responses.GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell proteome.However,the critical proteins driving these key mechanisms are still unknown.Here,we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses.TIA1-and TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection,expansion and differentiation into B-cell clones producing high-affinity antibodies.Mechanistically,TIA1 and TIAL1 control the transcriptional identity of dark-and light-zone GC B cells and enable timely expression of the prosurvival molecule MCL1.Thus,we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.
基金supported by the National Key Research and Development Program of China(grant no.2020YFA0907600)the National Natural Science Foundation of China(grant nos.31730102 and 32000184)+1 种基金the Natural Science Foundation of Shandong Province(grant no.ZR2020QC023)the China Postdoctoral Science Foundation(grant no.2020M672093).
文摘Chloroplasts evolved from an ancient cyanobacterial endosymbiont more than 1.5 billion years ago.During subsequent coevolution with the nuclear genome,the chloroplast genome has remained independent,albeit strongly reduced,with its own transcriptional machinery and distinct features,such as chloroplast-specific innovations in gene expression and complicated post-transcriptional processing.Light activates the expression of chloroplast genes via mechanisms that optimize photosynthesis,minimize photodamage,and prioritize energy investments.Over the past few years,studies have moved from describing phases of chloroplast gene expression to exploring the underlying mechanisms.In this review,we focus on recent advances and emerging principles that govern chloroplast gene expression in land plants.We discuss engineering of pentatricopeptide repeat proteins and its biotechnological effects on chloroplast RNA research;new techniques for characterizing the molecular mechanisms of chloroplast gene expression;and important aspects of chloroplast gene expression for improving crop yield and stress tolerance.We also discuss biological and mechanistic questions that remain to be answered in the future.