Plant organelles arose from two independent endosymbiosis events. Throughout evolutionary history, tight control of chloroplasts and mitochondria has been gained by the nucleus, which regulates most steps of organelle...Plant organelles arose from two independent endosymbiosis events. Throughout evolutionary history, tight control of chloroplasts and mitochondria has been gained by the nucleus, which regulates most steps of organelle genome expression and metabolism. In particular, RNA maturation, including RNA splicing, is highly dependent on nuclearly encoded splicing factors. Most introns in organelles are group II introns, whose catalytic mechanism closely resembles that of the nuclear spliceosome. Plant group II introns have lost the ability to self-splice in vivo and require nuclearly encoded proteins as cofactors. Since the first splicing factor was identified in chloroplasts more than 10 years ago, many other proteins have been shown to be involved in splicing of one or more introns in chloroplasts or mitochondria. These new proteins belong to a variety of different families of RNA binding proteins and provide new insights into ribonucleoprotein complexes and RNA splicing machineries in organelles. In this review, we describe how splicing factors, encoded by the nucleus and targeted to the organelles, take part in post-transcriptional steps in higher plant organelle gene expression. We go on to discuss the potential for these factors to regulate organelle gene expression.展开更多
Background: Extrinsic aging results from environmental stressors such as UVR or pollutants. While the effects of single pollutants are better understood, those of their combination remain poorly scrutinized. Objective...Background: Extrinsic aging results from environmental stressors such as UVR or pollutants. While the effects of single pollutants are better understood, those of their combination remain poorly scrutinized. Objective: Building on a study showing downregulation of several processes upon co-exposure to B[a]P and UVA, we investigated changes induced by epigenetic marks. Materials and Methods: Human primary fibroblasts and HaCaT cells were exposed to B[a]P and UVA. After 24 hours, exposed and unexposed cells were compared to assess DNA methylation. Focusing on HaCaT, multiplex assays enabled quantifying histone H3 modifications and evaluating four splicing factors (SRSF1, SRSF3, SFPQ, and SF3B1) by immunohistochemical labeling. The expression of keratinocyte-/fibroblast-relevant genes was assessed by RT-qPCR. Finally, the impact of an Arundo donax L. extract added 24 hours before B[a]P-UVA co-exposure was analyzed. Results: Exposure to B[a]P-UVA raised DNA methylation (HaCaT: ×3.6, fibroblasts: ×1.9), an increase prevented by the extract. In HaCaT cells, B[a]P-UVA increases the frequency of S10P (+38%). When exposure was preceded by extract treatment, the frequency of several methylations was impacted. B[a]P-UVA only induced the expression of SRSF1 and SFPQ in HaCaT (+46% and +34%). Treatment with the extract abolished this effect. Co-exposure increases the expression of inflammation-related genes (IL-1α, IL-1β) in HaCaT cells and decreases those of AQP3, KRT15, and SOD2. The extract has little effect on these changes. In primary fibroblasts, exposure to B[a]P-UVA lowered the expression of LOXL2, LUM, and TGFBR2 (−38%, −59%, and −51%, respectively), and the extract did not affect these modifications. Conclusion: Within 24 hours, a single B[a]P-UVA co-exposure changes epigenetic marks of skin cells but has only mild effects on gene expression. An Arundo donax L. extract can prevent part of the epigenetic marks’ changes and could stimulate the expression of some genes in primary fibroblasts.展开更多
The glucose metabolism is crucial for sustained brain activity as it provides energy and is a carbon source for multiple biomacromolecules;glucose metabolism decreases dramatically in Alzheimer’s disease(AD)and may b...The glucose metabolism is crucial for sustained brain activity as it provides energy and is a carbon source for multiple biomacromolecules;glucose metabolism decreases dramatically in Alzheimer’s disease(AD)and may be a fundamental cause for its development.Recent studies reveal that the alternative splicing events of certain genes effectively regulate several processes in glucose metabolism including insulin receptor,insulin-degrading enzyme,pyruvate kinase M,receptor for advanced glycation endproducts,and others,thereby,influencing glucose uptake,glycolysis,and advanced glycation end-products-mediated signaling pathways.Indeed,the discovery of aberrant alternative splicing that changes the proteomic diversity and protein activity in glucose metabolism has been pivotal in our understanding of AD development.In this review,we summarize the alternative splicing events of the glucose metabolism-related genes in AD pathology and highlight the crucial regulatory roles of splicing factors in the alternative splicing process.We also discuss the emerging therapeutic approaches for targeting splicing factors for AD treatment.展开更多
RNA splicing alterations are widespread and play critical roles in cancer pathogenesis and therapy.Lung cancer is highly heterogeneous and causes the most cancer-related deaths worldwide.Large-scale multi-omics studie...RNA splicing alterations are widespread and play critical roles in cancer pathogenesis and therapy.Lung cancer is highly heterogeneous and causes the most cancer-related deaths worldwide.Large-scale multi-omics studies have not only characterized the mutational landscapes but also discovered a plethora of transcriptional and post-transcriptional changes in lung cancer.Such resources have greatly facilitated the development of new diagnostic markers and therapeutic options over the past two decades.Intriguingly,altered RNA splicing has emerged as an important molecular feature and therapeutic target of lung cancer.In this review,we provide a brief overview of splicing dysregulation in lung cancer and summarize the recent progress on key splicing events and splicing factors that contribute to lung cancer pathogenesis.Moreover,we describe the general strategies targeting splicing alterations in lung cancer and highlight the potential of combining splicing modulation with currently approved therapies to combat this deadly disease.This review provides new mechanistic and therapeutic insights into splicing dysregulation in cancer.展开更多
Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that...Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention ofintronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulatepre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies.展开更多
Alternative splicing is the process of producing variably spliced mRNAs by choosing distinct combinations of splice sites within a messenger RNA precursor.This splicing enables mRNA from a single gene to synthesize di...Alternative splicing is the process of producing variably spliced mRNAs by choosing distinct combinations of splice sites within a messenger RNA precursor.This splicing enables mRNA from a single gene to synthesize different proteins,which have different cellular properties and functions and yet arise from the same single gene.A family of splicing factors,Serine-arginine rich proteins,are needed to initiate the assembly and activation of the spliceosome.Serine and arginine rich splicing factor 1,part of the arginine/serine-rich splicing factor protein family,can either activate or inhibit the splicing of mRNAs,depending on the phosphorylation status of the protein and its interaction partners.Considering that serine and arginine rich splicing factor 1 is either an activator or an inhibitor,this protein has been studied widely to identify its various roles in different diseases.Research has found that serine and arginine rich splicing factor 1 is a key target for neuroprotection,showing its promising potential use in therapeutics for neurodegenerative disorders.Furthermore,serine and arginine rich splicing factor 1 might be used to regulate cancer development and autoimmune diseases.In this review,we highlight how serine and arginine rich splicing factor 1 has been studied concerning neuroprotection.In addition,we draw attention to how serine and arginine rich splicing factor 1 is being studied in cancer and immunological disorders,as well as how serine and arginine rich splicing factor 1 acts outside the central or peripheral nervous system.展开更多
Alternative splicing allows a gene to produce multiple proteins and is the main source of human proteome diversity.Aberrant regulation of alternative splicing produces proteins with different structures and can lead t...Alternative splicing allows a gene to produce multiple proteins and is the main source of human proteome diversity.Aberrant regulation of alternative splicing produces proteins with different structures and can lead to altered protein function,inactivation,or deleterious variants,which can have severe effects on normal cellular function,leading to many diseases,including cancer.Alternative splicing abnormalities are often found in diseases,so alternative splicing is highly correlated with diseases and treatment.According to relevant statistics,breast cancer is an important factor that threatens women’s lives and health.A common sign of tumors in humans is abnormal alternative splicing.An increasing amount of evidence shows that abnormal alternative splicing plays an important role in the occurrence and development of breast cancer.At the same time,in the related treatment of breast cancer,alternative splicing can lead to the failure of existing treatment methods and induce drug resistance.Currently,targeted therapy is still the key strategy for breast cancer treatment.In this review,we discuss the five classifications of alternative splicing and aberrant alternative splicing in breast cancer.The role of alternative splicing in the drug resistance of breast cancer is also discussed.Evidence has shown that aberrant alternative splicing can lead to drug resistance to current therapies.Because splicing factors are involved in many aspects of cancer,splicing factors may provide a new strategy for cancer treatment and a powerful tool for progress in the fight against breast cancer.Antisense oligonucleotides form a double-stranded structure by complementary pairing with mRNA,which prevents the binding of mRNA and ribosomes,thus inhibiting protein synthesis.Therefore,after finding effective targets,antisense oligonucleotides can be applied in gene therapy,drug research and development,biological research,and other fields to improve therapeutic effects.展开更多
Hepatocellular carcinoma(HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors(TFs...Hepatocellular carcinoma(HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors(TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7 L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.展开更多
Spinal muscular atrophy(SMA)is a rare hereditary neuromuscular disease with a high lethality rate in infants.Variants in the homologous genes survival of motor neuron(SMN)1 and SMN2 have been reported to be SMA pathog...Spinal muscular atrophy(SMA)is a rare hereditary neuromuscular disease with a high lethality rate in infants.Variants in the homologous genes survival of motor neuron(SMN)1 and SMN2 have been reported to be SMA pathogenic factors.Previous studies showed that a highinclusion rate of SMN2 exon 7 increased SMN expression,which in turn reduced the severity of SMA.The inclusion rate of SMN2 exon 7 was higher in neural tissues than in non-neural tissues.Neuro-oncological ventral antigen(NOVA)is a splicing factor that is specifically and highly expressed in neurons.It plays a key role in nervous system development and in the induction of nervous system diseases.Howeve r,it remains unclear whether this splicing factor affects SMA.In this study,we analyzed the inclusion of SMN2 exon 7 in different tissues in a mouse model of SMA(genotype smn^(-/-)SMN2^(2 tg/0))and litter mate controls(genotype smn^(+/-)SMN2^(2 tg/0)).We found that inclusion level of SMN2 exon 7 was high in the brain and spinal co rd tissue,and that NOVA1 was also highly expressed in nervous system tissues.In addition,SMN2 exon 7 and NOVA1 were expressed synchronously in the central nervous system.We further investigated the effects of NOVA1 on disease and found that the number of neurons in the anterior horn of spinal cord decreased in the mouse model of SMA during postnatal days 1-7,and that NOVA1 expression levels in motor neurons decreased simultaneously as spinal muscular atrophy developed.We also found that in vitro expression of NOVA1 increased the inclusion of SMN2 exon 7 and expression ofthe SMN2 protein in the U87 MG cell line,whereas the opposite was observed when NOVA1 was knocked down.Finally,point mutation and RNA pull-down showed that the UCAC motif in SMN2 exon 7 plays a critical role in NOVA1 binding and promoting the inclusion of exon 7.Moreove r,CA was more essential for the inclusion of exon 7 than the order of Y residues in the motif.Collectively,these findings indicate that NOVA1 intera cts with the UCAC motif in exon 7 of SMN2,there 展开更多
It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteinswithpro-cancerproperties.These changes in alternative spl...It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteinswithpro-cancerproperties.These changes in alternative splicingcan arise frommutations or single-nucleotide polymorphisms(SNPs)within the DNA sequences of cancer-related genes,which can strongly affect the activity of splicing factors and influence the splice site choice.However,it is important to note that absence of mutations is not sufficient to prevent misleading choices in splice site selection.There is nowincreasing evidence to demonstrate that the expression profile of ten splicing factors(including SRs and hnRNPs)and eight RNA-binding proteins changes in breast cancer cells compared with normal cells.These modifications strongly influence the alternative splicing pattern of many cancer-related genes despite the absence of any detrimental mutations within their DNA sequences.Thus,a comprehensive assessment of the splicing factor status in breast cancer is important to provide insights into the mechanisms that lead to breast cancer development and metastasis.Whilst most studies focus on mutations that affect alternative splicing in cancer-related genes,this review focuses on splicing factors and RNA-binding proteins that are themselves deregulated in breast cancer and implicated in cancer-related alternative splicing events.展开更多
Long non-coding RNAs(lncRNAs) belong to a large and complex family of RNAs, which play many important roles in regulating gene expression. However, the mechanism underlying the dynamic expression of lncRNAs is still n...Long non-coding RNAs(lncRNAs) belong to a large and complex family of RNAs, which play many important roles in regulating gene expression. However, the mechanism underlying the dynamic expression of lncRNAs is still not very clear. In order to identify lncRNAs and clarify the mechanisms involved, we collected basic information and highlighted the mechanisms underlying lncRNA expression and regulation. Overall, lncRNAs are regulated by several similar transcription factors and protein-coding genes. Epigenetic modification(DNA methylation and histone modification) can also downregulate lncRNA levels in tissues and cells. Moreover, lncRNAs may be degraded or cleaved via interaction with miRNAs and miRNAassociated protein complexes. Furthermore, alternative RNA splicing(AS) may play a significant role in the post-transcriptional regulation of lncRNAs.展开更多
文摘Plant organelles arose from two independent endosymbiosis events. Throughout evolutionary history, tight control of chloroplasts and mitochondria has been gained by the nucleus, which regulates most steps of organelle genome expression and metabolism. In particular, RNA maturation, including RNA splicing, is highly dependent on nuclearly encoded splicing factors. Most introns in organelles are group II introns, whose catalytic mechanism closely resembles that of the nuclear spliceosome. Plant group II introns have lost the ability to self-splice in vivo and require nuclearly encoded proteins as cofactors. Since the first splicing factor was identified in chloroplasts more than 10 years ago, many other proteins have been shown to be involved in splicing of one or more introns in chloroplasts or mitochondria. These new proteins belong to a variety of different families of RNA binding proteins and provide new insights into ribonucleoprotein complexes and RNA splicing machineries in organelles. In this review, we describe how splicing factors, encoded by the nucleus and targeted to the organelles, take part in post-transcriptional steps in higher plant organelle gene expression. We go on to discuss the potential for these factors to regulate organelle gene expression.
文摘Background: Extrinsic aging results from environmental stressors such as UVR or pollutants. While the effects of single pollutants are better understood, those of their combination remain poorly scrutinized. Objective: Building on a study showing downregulation of several processes upon co-exposure to B[a]P and UVA, we investigated changes induced by epigenetic marks. Materials and Methods: Human primary fibroblasts and HaCaT cells were exposed to B[a]P and UVA. After 24 hours, exposed and unexposed cells were compared to assess DNA methylation. Focusing on HaCaT, multiplex assays enabled quantifying histone H3 modifications and evaluating four splicing factors (SRSF1, SRSF3, SFPQ, and SF3B1) by immunohistochemical labeling. The expression of keratinocyte-/fibroblast-relevant genes was assessed by RT-qPCR. Finally, the impact of an Arundo donax L. extract added 24 hours before B[a]P-UVA co-exposure was analyzed. Results: Exposure to B[a]P-UVA raised DNA methylation (HaCaT: ×3.6, fibroblasts: ×1.9), an increase prevented by the extract. In HaCaT cells, B[a]P-UVA increases the frequency of S10P (+38%). When exposure was preceded by extract treatment, the frequency of several methylations was impacted. B[a]P-UVA only induced the expression of SRSF1 and SFPQ in HaCaT (+46% and +34%). Treatment with the extract abolished this effect. Co-exposure increases the expression of inflammation-related genes (IL-1α, IL-1β) in HaCaT cells and decreases those of AQP3, KRT15, and SOD2. The extract has little effect on these changes. In primary fibroblasts, exposure to B[a]P-UVA lowered the expression of LOXL2, LUM, and TGFBR2 (−38%, −59%, and −51%, respectively), and the extract did not affect these modifications. Conclusion: Within 24 hours, a single B[a]P-UVA co-exposure changes epigenetic marks of skin cells but has only mild effects on gene expression. An Arundo donax L. extract can prevent part of the epigenetic marks’ changes and could stimulate the expression of some genes in primary fibroblasts.
基金granted by the joint foundation of Luzhou Government and Southwest Medical University(No.2018LZXNYD-ZK05)the Talent Development Project of the Affiliated Hospital of Southwest Medical University.
文摘The glucose metabolism is crucial for sustained brain activity as it provides energy and is a carbon source for multiple biomacromolecules;glucose metabolism decreases dramatically in Alzheimer’s disease(AD)and may be a fundamental cause for its development.Recent studies reveal that the alternative splicing events of certain genes effectively regulate several processes in glucose metabolism including insulin receptor,insulin-degrading enzyme,pyruvate kinase M,receptor for advanced glycation endproducts,and others,thereby,influencing glucose uptake,glycolysis,and advanced glycation end-products-mediated signaling pathways.Indeed,the discovery of aberrant alternative splicing that changes the proteomic diversity and protein activity in glucose metabolism has been pivotal in our understanding of AD development.In this review,we summarize the alternative splicing events of the glucose metabolism-related genes in AD pathology and highlight the crucial regulatory roles of splicing factors in the alternative splicing process.We also discuss the emerging therapeutic approaches for targeting splicing factors for AD treatment.
基金This work was supported by the National Natural Science Foundation of China(Nos.81871878,31371299)the Shanghai Municipal Natural Science Fund(No.20ZR1406500)the Innovation Research Team of High-level Local Universities in Shanghai.
文摘RNA splicing alterations are widespread and play critical roles in cancer pathogenesis and therapy.Lung cancer is highly heterogeneous and causes the most cancer-related deaths worldwide.Large-scale multi-omics studies have not only characterized the mutational landscapes but also discovered a plethora of transcriptional and post-transcriptional changes in lung cancer.Such resources have greatly facilitated the development of new diagnostic markers and therapeutic options over the past two decades.Intriguingly,altered RNA splicing has emerged as an important molecular feature and therapeutic target of lung cancer.In this review,we provide a brief overview of splicing dysregulation in lung cancer and summarize the recent progress on key splicing events and splicing factors that contribute to lung cancer pathogenesis.Moreover,we describe the general strategies targeting splicing alterations in lung cancer and highlight the potential of combining splicing modulation with currently approved therapies to combat this deadly disease.This review provides new mechanistic and therapeutic insights into splicing dysregulation in cancer.
基金Supported by The Agreement between FIMA and the "UTE project CIMA"Red Temática de Investigación Cooperativa en Cáncer RD06 00200061 (to Berasain C and ávila MA)Ciberehd (to Prieto J) from Instituto de Salud Carlos Ⅲ,Grants FIS PI070392 and PI070402 from Ministerio de Sanidad y Con-sumo
文摘Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention ofintronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulatepre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies.
文摘Alternative splicing is the process of producing variably spliced mRNAs by choosing distinct combinations of splice sites within a messenger RNA precursor.This splicing enables mRNA from a single gene to synthesize different proteins,which have different cellular properties and functions and yet arise from the same single gene.A family of splicing factors,Serine-arginine rich proteins,are needed to initiate the assembly and activation of the spliceosome.Serine and arginine rich splicing factor 1,part of the arginine/serine-rich splicing factor protein family,can either activate or inhibit the splicing of mRNAs,depending on the phosphorylation status of the protein and its interaction partners.Considering that serine and arginine rich splicing factor 1 is either an activator or an inhibitor,this protein has been studied widely to identify its various roles in different diseases.Research has found that serine and arginine rich splicing factor 1 is a key target for neuroprotection,showing its promising potential use in therapeutics for neurodegenerative disorders.Furthermore,serine and arginine rich splicing factor 1 might be used to regulate cancer development and autoimmune diseases.In this review,we highlight how serine and arginine rich splicing factor 1 has been studied concerning neuroprotection.In addition,we draw attention to how serine and arginine rich splicing factor 1 is being studied in cancer and immunological disorders,as well as how serine and arginine rich splicing factor 1 acts outside the central or peripheral nervous system.
文摘Alternative splicing allows a gene to produce multiple proteins and is the main source of human proteome diversity.Aberrant regulation of alternative splicing produces proteins with different structures and can lead to altered protein function,inactivation,or deleterious variants,which can have severe effects on normal cellular function,leading to many diseases,including cancer.Alternative splicing abnormalities are often found in diseases,so alternative splicing is highly correlated with diseases and treatment.According to relevant statistics,breast cancer is an important factor that threatens women’s lives and health.A common sign of tumors in humans is abnormal alternative splicing.An increasing amount of evidence shows that abnormal alternative splicing plays an important role in the occurrence and development of breast cancer.At the same time,in the related treatment of breast cancer,alternative splicing can lead to the failure of existing treatment methods and induce drug resistance.Currently,targeted therapy is still the key strategy for breast cancer treatment.In this review,we discuss the five classifications of alternative splicing and aberrant alternative splicing in breast cancer.The role of alternative splicing in the drug resistance of breast cancer is also discussed.Evidence has shown that aberrant alternative splicing can lead to drug resistance to current therapies.Because splicing factors are involved in many aspects of cancer,splicing factors may provide a new strategy for cancer treatment and a powerful tool for progress in the fight against breast cancer.Antisense oligonucleotides form a double-stranded structure by complementary pairing with mRNA,which prevents the binding of mRNA and ribosomes,thus inhibiting protein synthesis.Therefore,after finding effective targets,antisense oligonucleotides can be applied in gene therapy,drug research and development,biological research,and other fields to improve therapeutic effects.
基金Supported by Russian Foundation for Basic Research,contract No.18-34-00816\18
文摘Hepatocellular carcinoma(HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors(TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7 L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.
基金the National Natural Science Foundation of China,No.32000841(to JJS)a grant from Science and Technology Project of Nantong of Jiangsu Province,No.JC2018090(to LCW)a grant from Graduate Research and Innovation Project of Jiangsu Province,No.KYCX18-2415(to LLD)。
文摘Spinal muscular atrophy(SMA)is a rare hereditary neuromuscular disease with a high lethality rate in infants.Variants in the homologous genes survival of motor neuron(SMN)1 and SMN2 have been reported to be SMA pathogenic factors.Previous studies showed that a highinclusion rate of SMN2 exon 7 increased SMN expression,which in turn reduced the severity of SMA.The inclusion rate of SMN2 exon 7 was higher in neural tissues than in non-neural tissues.Neuro-oncological ventral antigen(NOVA)is a splicing factor that is specifically and highly expressed in neurons.It plays a key role in nervous system development and in the induction of nervous system diseases.Howeve r,it remains unclear whether this splicing factor affects SMA.In this study,we analyzed the inclusion of SMN2 exon 7 in different tissues in a mouse model of SMA(genotype smn^(-/-)SMN2^(2 tg/0))and litter mate controls(genotype smn^(+/-)SMN2^(2 tg/0)).We found that inclusion level of SMN2 exon 7 was high in the brain and spinal co rd tissue,and that NOVA1 was also highly expressed in nervous system tissues.In addition,SMN2 exon 7 and NOVA1 were expressed synchronously in the central nervous system.We further investigated the effects of NOVA1 on disease and found that the number of neurons in the anterior horn of spinal cord decreased in the mouse model of SMA during postnatal days 1-7,and that NOVA1 expression levels in motor neurons decreased simultaneously as spinal muscular atrophy developed.We also found that in vitro expression of NOVA1 increased the inclusion of SMN2 exon 7 and expression ofthe SMN2 protein in the U87 MG cell line,whereas the opposite was observed when NOVA1 was knocked down.Finally,point mutation and RNA pull-down showed that the UCAC motif in SMN2 exon 7 plays a critical role in NOVA1 binding and promoting the inclusion of exon 7.Moreove r,CA was more essential for the inclusion of exon 7 than the order of Y residues in the motif.Collectively,these findings indicate that NOVA1 intera cts with the UCAC motif in exon 7 of SMN2,there
基金This work was supported by the Royal Victoria Infirmary Breast Cancer Appeal(Reference number BH136312).
文摘It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteinswithpro-cancerproperties.These changes in alternative splicingcan arise frommutations or single-nucleotide polymorphisms(SNPs)within the DNA sequences of cancer-related genes,which can strongly affect the activity of splicing factors and influence the splice site choice.However,it is important to note that absence of mutations is not sufficient to prevent misleading choices in splice site selection.There is nowincreasing evidence to demonstrate that the expression profile of ten splicing factors(including SRs and hnRNPs)and eight RNA-binding proteins changes in breast cancer cells compared with normal cells.These modifications strongly influence the alternative splicing pattern of many cancer-related genes despite the absence of any detrimental mutations within their DNA sequences.Thus,a comprehensive assessment of the splicing factor status in breast cancer is important to provide insights into the mechanisms that lead to breast cancer development and metastasis.Whilst most studies focus on mutations that affect alternative splicing in cancer-related genes,this review focuses on splicing factors and RNA-binding proteins that are themselves deregulated in breast cancer and implicated in cancer-related alternative splicing events.
文摘Long non-coding RNAs(lncRNAs) belong to a large and complex family of RNAs, which play many important roles in regulating gene expression. However, the mechanism underlying the dynamic expression of lncRNAs is still not very clear. In order to identify lncRNAs and clarify the mechanisms involved, we collected basic information and highlighted the mechanisms underlying lncRNA expression and regulation. Overall, lncRNAs are regulated by several similar transcription factors and protein-coding genes. Epigenetic modification(DNA methylation and histone modification) can also downregulate lncRNA levels in tissues and cells. Moreover, lncRNAs may be degraded or cleaved via interaction with miRNAs and miRNAassociated protein complexes. Furthermore, alternative RNA splicing(AS) may play a significant role in the post-transcriptional regulation of lncRNAs.
