RNA folds into intricate structures that are crucial for its functions and regulations. To date, a multitude of approaches for probing structures of the whole transcriptome, i.e., RNA struc- turomes, have been develop...RNA folds into intricate structures that are crucial for its functions and regulations. To date, a multitude of approaches for probing structures of the whole transcriptome, i.e., RNA struc- turomes, have been developed. Applications of these approaches to different cell lines and tissues have generated a rich resource for the study of RNA structure-function relationships at a systems biology level. In this review, we first introduce the designs of these methods and their applications to study different RNA structuromes. We emphasize their technological differences especially their unique advantages and caveats. We then summarize the structural insights in RNA functions and regulations obtained from the studies of RNA structuromes. And finally, we propose potential directions for future improvements and studies.展开更多
Neurodegeneration and traumatic brain injuries are leading causes of disability and present an enormous disease burden both in terms of patient suffering and healthcare cost.Treatment of brain lesions remains as a maj...Neurodegeneration and traumatic brain injuries are leading causes of disability and present an enormous disease burden both in terms of patient suffering and healthcare cost.Treatment of brain lesions remains as a major challenge in medicine largely because of the limited regenerative capacity of the adult brain.展开更多
Safe and effective gene therapy approaches require targeted tissue-specific transfer of a therapeutic transgene.Besides traditional approaches, such as transcriptional and transductional targeting, micro RNA-dependent...Safe and effective gene therapy approaches require targeted tissue-specific transfer of a therapeutic transgene.Besides traditional approaches, such as transcriptional and transductional targeting, micro RNA-dependent posttranscriptional suppression of transgene expression has been emerging as powerful new technology to increase the specificity of vector-mediated transgene expression. Micro RNAs are small non-coding RNAs and often expressed in a tissue-, lineage-, activation- or differentiation-specific pattern. They typically regulate gene expression by binding to imperfectly complementary sequences in the 3' untranslated region(UTR) of the m RNA. To control exogenous transgene expression, tandem repeats of artificial micro RNA target sites are usually incorporated into the 3' UTR of the transgene expression cassette, leading to subsequent degradation of transgene m RNA in cel s expressing the corresponding micro RNA. This targeting strategy, first shown for lentiviral vectors in antigen presenting cells, has now been used for tissue-specific expression of vector-encoded therapeutic transgenes, to reduce immune response against the transgene, to control virus tropism for oncolytic virotherapy, to increase safety of live attenuated virus vaccines and to identify and select cell subsets for pluripotent stem cell therapies, respectively. This review provides an introduction into the technical mechanism underlying micro RNA-regulation, highlights new developments in this field and gives an overview of applications of micro RNA-regulated viral vectors for cardiac, suicide gene cancer and hematopoietic stem cell therapy, as well as for treatment of neurological and eye diseases.展开更多
The dorsal lingual epithelium,which is composed of taste buds and keratinocytes differentiated from K14^(+)basal cells,discriminates taste compounds and maintains the epithelial barrier.N6-methyladenosine(m^(6)A)is th...The dorsal lingual epithelium,which is composed of taste buds and keratinocytes differentiated from K14^(+)basal cells,discriminates taste compounds and maintains the epithelial barrier.N6-methyladenosine(m^(6)A)is the most abundant mRNA modification in eukaryotic cells.How METTL3-mediated m^(6)A modification regulates K14^(+)basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear.Here we show knockout of Mettl3 in K14^(+)cells reduced the taste buds and enhanced keratinocytes.Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds.Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization,but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery.Mechanically,we revealed that the most frequent m^(6)A modifications were enriched in Hippo and Wnt signaling,and specific peaks were observed near the stop codons of Lats1 and FZD7.Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.展开更多
Mitochondria serve as the powerhouse of cells,respond to cellular demands and stressors,and play an essential role in cell signaling,differentiation,and survival.Aberrant mitochondria function has been linked to diver...Mitochondria serve as the powerhouse of cells,respond to cellular demands and stressors,and play an essential role in cell signaling,differentiation,and survival.Aberrant mitochondria function has been linked to diverse and complex human diseases such as neurodegenerative diseases,cancers,myopathies,premature aging,and metabolic syndromes(Nunnari and Suomalainen,2012).展开更多
Posttranscriptional regulations of different types of RNA,including rRNA,tRNA,mRNA and ncRNA are widely involved in normal physiology and diseases.m RNA,as the intermediary product between gene and protein,whose postt...Posttranscriptional regulations of different types of RNA,including rRNA,tRNA,mRNA and ncRNA are widely involved in normal physiology and diseases.m RNA,as the intermediary product between gene and protein,whose posttranscriptional regulations such as alternative splicing,alternative polyadenylation and modifications impact its coded protein expression and functions.However,the functional significance and therapeutic potential of RNA posttranscriptional regulations are not well studied due to the lack of suitable RNA engineering platforms.The discovery of a novel CRISPR-Cas system termed CRISPR-Cas13 in 2015 that specifically targets RNA templates brought a new role to CRISPR to target and edit RNA with high specificity,which opened a new era of RNA manipulations to some degree.This review will summarize the emerging applications of the catalytically inactive CRISPR-Cas13 system(CRISPR-dCas13)in mRNA engineering and highlight the prospection of the CRISPR-dCas13 system for other RNA modification regulations and its therapeutic potential.展开更多
Background:RNA binding proteins(RBPs)play essential roles in the regulation of RNA metabolism.Recent studies have disclosed that RBPs achieve their functions via binding to their targets in a position-dependent patter...Background:RNA binding proteins(RBPs)play essential roles in the regulation of RNA metabolism.Recent studies have disclosed that RBPs achieve their functions via binding to their targets in a position-dependent pattern on RNAs.However,few studies have systematially addressed the associations between the RBP's functions and their positional binding preferences.Methods:Here,we present large-scale analyses on the functional targets of human RBPs by integrating the enhanced cross-linking and immunoprecipitation followed by sequencing(eCLIP-seq)datasets and the shRNA knockdown followed by RNA-seq datasets that are deposited in the integrated ENCyclopedia of DNA Elements in the human genome(ENCODE)data portal.Results:We found that(1)binding to the translation termination site and the 3'untranslated region is important to most human RBP's in the RNA decay regulation;(2)RBPs’binding and regulation follow a cell-ty pe specific pattern.Conclusions:These analysis results show the strong relationship between the binding position and the functions of RBPs,which provides novel insights into the RBPs'regulation mechanisms.展开更多
The global incidence of depression is progressively on the rise and tends to occur more in younger generations,however the pathogenesis of the disease is unclear.Meanwhile,epigenetics is a modification which produces ...The global incidence of depression is progressively on the rise and tends to occur more in younger generations,however the pathogenesis of the disease is unclear.Meanwhile,epigenetics is a modification which produces heritable alterations in the DNA sequence,which ultimately manifest in phenotypic differences.It has been suggested that the onset and development of depression can be tentatively explained by the combination of epigenetic and environmental factors.This paper reviews epigenetic changes in depression in the context of environmental factors,including DNA methylation modifications,histone modifications,and non-coding RNA regulation.An epigenetic-based therapeutic outlook was also proposed in this paper,which initially elucidates the epigenetic mechanisms underlying the pathogenesis of depressions and provides a theoretical basis for the treatment of depression.展开更多
Background Aldosterone blockers could reduce the incidence of ventricular arrhythmias in myocardial infarction(MI) patients by regulating hyperpolarization-activated cyclic nucleotide-gated channel(HCN) expression...Background Aldosterone blockers could reduce the incidence of ventricular arrhythmias in myocardial infarction(MI) patients by regulating hyperpolarization-activated cyclic nucleotide-gated channel(HCN) expression.But the mechanism underling HCN expression is unclear.Methods Eighteen rats surviving 24 hours postMI were randomly divided into 3 groups:MI,spironolactone,and spironolactone + antagomir-133(mi RNA-133suppression).Sham group rats had a suture loosely tied around the left coronary artery,without ligation.HCN2 and HCN4 protein and m RNA level,and mi RNA-133 level in the border zone of post-MI 1 week myocardium were measured.Results Spironolactone significantly increased mi RNA-133 levels and down-regulated HCN2 and HCN4 at both m RNA and protein levels in post-MI border zone myocardium.Antagomir-133 reduced the effects of spironolactone on HCN2 and HCN4 protein levels.Conclusions The results suggest that mi RNA-133 is involved in spironolactone induced HCN expression,and partially contributed to post-MI ventricular arrhythmias.展开更多
Due to global climate change, temperature stress has become one of the primary causes of crop losses worldwide. Much progress has been made in unraveling the complex stress response mechanisms in plants, particularly ...Due to global climate change, temperature stress has become one of the primary causes of crop losses worldwide. Much progress has been made in unraveling the complex stress response mechanisms in plants, particularly in the identification of temperature stress responsive protein-coding genes. Recently discovered micro RNAs(mi RNAs) and endogenous small-interfering RNAs(si RNAs) have also been demonstrated as simportant players in plant temperature stress response.Using high-throughput sequencing, many small RNAs,especially mi RNAs, have been identified to be triggered by cold or heat. Subsequently, several studies have shown an important functional role for these small RNAs in cold or heat tolerance. These findings greatly broaden our understanding of endogenous small RNAs in plant stress response control. Here, we highlight new findings regarding the roles of mi RNAs and si RNAs in plant temperature stress response and acclimation. We also review the current understanding of the regulatory mechanisms of small RNAs in temperature stress response, and explore the outlook for the use of these small RNAs in molecular breeding for improvement of temperature stress tolerance in plants.展开更多
Methylation of adenosine base on the nitrogen-6 position (N6-methyladenosine, m^6A) is the most common and abundant modification on mRNA transcripts. This post-transcriptional modification was first described in the...Methylation of adenosine base on the nitrogen-6 position (N6-methyladenosine, m^6A) is the most common and abundant modification on mRNA transcripts. This post-transcriptional modification was first described in the 1970s in hepatoma cells (Desrosiers et al., 1974).展开更多
Rice(Oryza sativa L.)is a major food crop for more than half of the world’s population.Therefore,increasing rice production is of great importance.The successful development of hybrid rice in the 1970s was an importa...Rice(Oryza sativa L.)is a major food crop for more than half of the world’s population.Therefore,increasing rice production is of great importance.The successful development of hybrid rice in the 1970s was an important achievement for increasing yield potential,since hybrid rice varieties produce higher yields than inbred varieties(Cheng et al.,2007).In plants,male sterility refers to the inability of producing dehiscent anthers and functional pollen(Chen and Liu,2014).展开更多
Recently an article published in Molecular Cell reveals the mechanism of a nuclear N6-methyladenosine(m^6A)reader,the YTH domain-containing protein 1(YTHDC1),in regulating pre-m RNA splicing[1].Meanwhile,two addit...Recently an article published in Molecular Cell reveals the mechanism of a nuclear N6-methyladenosine(m^6A)reader,the YTH domain-containing protein 1(YTHDC1),in regulating pre-m RNA splicing[1].Meanwhile,two additional articles published in Nature and Nature Chemical Biology report the展开更多
基金supported by the National Natural Science Foundation of China(Grant No.31671355)the National Thousand Young Talents Program of China to QCZ
文摘RNA folds into intricate structures that are crucial for its functions and regulations. To date, a multitude of approaches for probing structures of the whole transcriptome, i.e., RNA struc- turomes, have been developed. Applications of these approaches to different cell lines and tissues have generated a rich resource for the study of RNA structure-function relationships at a systems biology level. In this review, we first introduce the designs of these methods and their applications to study different RNA structuromes. We emphasize their technological differences especially their unique advantages and caveats. We then summarize the structural insights in RNA functions and regulations obtained from the studies of RNA structuromes. And finally, we propose potential directions for future improvements and studies.
文摘Neurodegeneration and traumatic brain injuries are leading causes of disability and present an enormous disease burden both in terms of patient suffering and healthcare cost.Treatment of brain lesions remains as a major challenge in medicine largely because of the limited regenerative capacity of the adult brain.
基金Supported by The Deutsche Forschungsgemeinschaft,Nos.FE785/2-2 and FE785/4-1the Bundesministerium für Bildung und Entwicklung,No.031A331
文摘Safe and effective gene therapy approaches require targeted tissue-specific transfer of a therapeutic transgene.Besides traditional approaches, such as transcriptional and transductional targeting, micro RNA-dependent posttranscriptional suppression of transgene expression has been emerging as powerful new technology to increase the specificity of vector-mediated transgene expression. Micro RNAs are small non-coding RNAs and often expressed in a tissue-, lineage-, activation- or differentiation-specific pattern. They typically regulate gene expression by binding to imperfectly complementary sequences in the 3' untranslated region(UTR) of the m RNA. To control exogenous transgene expression, tandem repeats of artificial micro RNA target sites are usually incorporated into the 3' UTR of the transgene expression cassette, leading to subsequent degradation of transgene m RNA in cel s expressing the corresponding micro RNA. This targeting strategy, first shown for lentiviral vectors in antigen presenting cells, has now been used for tissue-specific expression of vector-encoded therapeutic transgenes, to reduce immune response against the transgene, to control virus tropism for oncolytic virotherapy, to increase safety of live attenuated virus vaccines and to identify and select cell subsets for pluripotent stem cell therapies, respectively. This review provides an introduction into the technical mechanism underlying micro RNA-regulation, highlights new developments in this field and gives an overview of applications of micro RNA-regulated viral vectors for cardiac, suicide gene cancer and hematopoietic stem cell therapy, as well as for treatment of neurological and eye diseases.
基金supported by the National Natural Science Foundation of China(81970913 and 82125006)。
文摘The dorsal lingual epithelium,which is composed of taste buds and keratinocytes differentiated from K14^(+)basal cells,discriminates taste compounds and maintains the epithelial barrier.N6-methyladenosine(m^(6)A)is the most abundant mRNA modification in eukaryotic cells.How METTL3-mediated m^(6)A modification regulates K14^(+)basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear.Here we show knockout of Mettl3 in K14^(+)cells reduced the taste buds and enhanced keratinocytes.Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds.Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization,but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery.Mechanically,we revealed that the most frequent m^(6)A modifications were enriched in Hippo and Wnt signaling,and specific peaks were observed near the stop codons of Lats1 and FZD7.Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.
基金Supported by an endowment to JES from Cardinal Hill Rehabilitation Hospital
文摘Mitochondria serve as the powerhouse of cells,respond to cellular demands and stressors,and play an essential role in cell signaling,differentiation,and survival.Aberrant mitochondria function has been linked to diverse and complex human diseases such as neurodegenerative diseases,cancers,myopathies,premature aging,and metabolic syndromes(Nunnari and Suomalainen,2012).
文摘Posttranscriptional regulations of different types of RNA,including rRNA,tRNA,mRNA and ncRNA are widely involved in normal physiology and diseases.m RNA,as the intermediary product between gene and protein,whose posttranscriptional regulations such as alternative splicing,alternative polyadenylation and modifications impact its coded protein expression and functions.However,the functional significance and therapeutic potential of RNA posttranscriptional regulations are not well studied due to the lack of suitable RNA engineering platforms.The discovery of a novel CRISPR-Cas system termed CRISPR-Cas13 in 2015 that specifically targets RNA templates brought a new role to CRISPR to target and edit RNA with high specificity,which opened a new era of RNA manipulations to some degree.This review will summarize the emerging applications of the catalytically inactive CRISPR-Cas13 system(CRISPR-dCas13)in mRNA engineering and highlight the prospection of the CRISPR-dCas13 system for other RNA modification regulations and its therapeutic potential.
基金Z.O.acknowledges the National Institute of General Medical Sciences(https://www.nigms.nih.gov/)grant R35GM124998.
文摘Background:RNA binding proteins(RBPs)play essential roles in the regulation of RNA metabolism.Recent studies have disclosed that RBPs achieve their functions via binding to their targets in a position-dependent pattern on RNAs.However,few studies have systematially addressed the associations between the RBP's functions and their positional binding preferences.Methods:Here,we present large-scale analyses on the functional targets of human RBPs by integrating the enhanced cross-linking and immunoprecipitation followed by sequencing(eCLIP-seq)datasets and the shRNA knockdown followed by RNA-seq datasets that are deposited in the integrated ENCyclopedia of DNA Elements in the human genome(ENCODE)data portal.Results:We found that(1)binding to the translation termination site and the 3'untranslated region is important to most human RBP's in the RNA decay regulation;(2)RBPs’binding and regulation follow a cell-ty pe specific pattern.Conclusions:These analysis results show the strong relationship between the binding position and the functions of RBPs,which provides novel insights into the RBPs'regulation mechanisms.
文摘The global incidence of depression is progressively on the rise and tends to occur more in younger generations,however the pathogenesis of the disease is unclear.Meanwhile,epigenetics is a modification which produces heritable alterations in the DNA sequence,which ultimately manifest in phenotypic differences.It has been suggested that the onset and development of depression can be tentatively explained by the combination of epigenetic and environmental factors.This paper reviews epigenetic changes in depression in the context of environmental factors,including DNA methylation modifications,histone modifications,and non-coding RNA regulation.An epigenetic-based therapeutic outlook was also proposed in this paper,which initially elucidates the epigenetic mechanisms underlying the pathogenesis of depressions and provides a theoretical basis for the treatment of depression.
基金National Natural Science Foundation of China(No.NSFC81100088)
文摘Background Aldosterone blockers could reduce the incidence of ventricular arrhythmias in myocardial infarction(MI) patients by regulating hyperpolarization-activated cyclic nucleotide-gated channel(HCN) expression.But the mechanism underling HCN expression is unclear.Methods Eighteen rats surviving 24 hours postMI were randomly divided into 3 groups:MI,spironolactone,and spironolactone + antagomir-133(mi RNA-133suppression).Sham group rats had a suture loosely tied around the left coronary artery,without ligation.HCN2 and HCN4 protein and m RNA level,and mi RNA-133 level in the border zone of post-MI 1 week myocardium were measured.Results Spironolactone significantly increased mi RNA-133 levels and down-regulated HCN2 and HCN4 at both m RNA and protein levels in post-MI border zone myocardium.Antagomir-133 reduced the effects of spironolactone on HCN2 and HCN4 protein levels.Conclusions The results suggest that mi RNA-133 is involved in spironolactone induced HCN expression,and partially contributed to post-MI ventricular arrhythmias.
基金supported by the National Youth Science Foundation of China(31201198)the Key Project of Guangdong Scientific and Technological Plan(2015B020231002)the Guangdong Modern Agricultural Creation Team Project(2016LM2148)
文摘Due to global climate change, temperature stress has become one of the primary causes of crop losses worldwide. Much progress has been made in unraveling the complex stress response mechanisms in plants, particularly in the identification of temperature stress responsive protein-coding genes. Recently discovered micro RNAs(mi RNAs) and endogenous small-interfering RNAs(si RNAs) have also been demonstrated as simportant players in plant temperature stress response.Using high-throughput sequencing, many small RNAs,especially mi RNAs, have been identified to be triggered by cold or heat. Subsequently, several studies have shown an important functional role for these small RNAs in cold or heat tolerance. These findings greatly broaden our understanding of endogenous small RNAs in plant stress response control. Here, we highlight new findings regarding the roles of mi RNAs and si RNAs in plant temperature stress response and acclimation. We also review the current understanding of the regulatory mechanisms of small RNAs in temperature stress response, and explore the outlook for the use of these small RNAs in molecular breeding for improvement of temperature stress tolerance in plants.
文摘Methylation of adenosine base on the nitrogen-6 position (N6-methyladenosine, m^6A) is the most common and abundant modification on mRNA transcripts. This post-transcriptional modification was first described in the 1970s in hepatoma cells (Desrosiers et al., 1974).
文摘Rice(Oryza sativa L.)is a major food crop for more than half of the world’s population.Therefore,increasing rice production is of great importance.The successful development of hybrid rice in the 1970s was an important achievement for increasing yield potential,since hybrid rice varieties produce higher yields than inbred varieties(Cheng et al.,2007).In plants,male sterility refers to the inability of producing dehiscent anthers and functional pollen(Chen and Liu,2014).
基金supported by the National Basic Research Program of China (973 ProgramGrant No.2014CB964900)the National Natural Science Foundation of China (Grant Nos.21432002,21372022,and 21210003)
文摘Recently an article published in Molecular Cell reveals the mechanism of a nuclear N6-methyladenosine(m^6A)reader,the YTH domain-containing protein 1(YTHDC1),in regulating pre-m RNA splicing[1].Meanwhile,two additional articles published in Nature and Nature Chemical Biology report the