Genome-wide identification of RNA editing in seven porcine tissues by matched DNA and RNA high-throughput sequencing
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摘要
Background: RNA editing is a co/posttranscriptional modification mechanism that increases the diversity of transcripts, with potential functional consequences. The advent of next-generation sequencing technologies has enabled the identification of RNA edits at unprecedented throughput and resolution. However, our knowledge of RNA editing in swine is still limited.Results: Here, we utilized RES-Scanner to identify RNA editing sites in the brain, subcutaneous fat, heart, liver,muscle, lung and ovary in three 180-day-old Large White gilts based on matched strand-specific RNA sequencing and whole-genome resequencing datasets. In total, we identified 74863 editing sites, and 92.1% of these sites caused adenosine-to-guanosine(A-to-G) conversion. Most A-to-G sites were located in noncoding regions and generally had low editing levels. In total, 151 A-to-G sites were detected in coding regions(CDS), including 94 sites that could lead to nonsynonymous amino acid changes. We provide further evidence supporting a previous observation that pig transcriptomes are highly editable at PRE-1 elements. The number of A-to-G editing sites ranged from 4155(muscle) to 25001(brain) across the seven tissues. The expression levels of the ADAR enzymes could explain some but not all of this variation across tissues. The functional analysis of the genes with tissuespecific editing sites in each tissue revealed that RNA editing might play important roles in tissue function.Specifically, more pathways showed significant enrichment in the fat and liver than in other tissues, while no pathway was enriched in the muscle.Conclusions: This study identified a total of 74863 nonredundant RNA editing sites in seven tissues and revealed the potential importance of RNA editing in tissue function. Our findings largely extend the porcine editome and enhance our understanding of RNA editing in swine.
Background: RNA editing is a co/posttranscriptional modification mechanism that increases the diversity of transcripts, with potential functional consequences. The advent of next-generation sequencing technologies has enabled the identification of RNA edits at unprecedented throughput and resolution. However, our knowledge of RNA editing in swine is still limited.Results: Here, we utilized RES-Scanner to identify RNA editing sites in the brain, subcutaneous fat, heart, liver,muscle, lung and ovary in three 180-day-old Large White gilts based on matched strand-specific RNA sequencing and whole-genome resequencing datasets. In total, we identified 74863 editing sites, and 92.1% of these sites caused adenosine-to-guanosine(A-to-G) conversion. Most A-to-G sites were located in noncoding regions and generally had low editing levels. In total, 151 A-to-G sites were detected in coding regions(CDS), including 94 sites that could lead to nonsynonymous amino acid changes. We provide further evidence supporting a previous observation that pig transcriptomes are highly editable at PRE-1 elements. The number of A-to-G editing sites ranged from 4155(muscle) to 25001(brain) across the seven tissues. The expression levels of the ADAR enzymes could explain some but not all of this variation across tissues. The functional analysis of the genes with tissuespecific editing sites in each tissue revealed that RNA editing might play important roles in tissue function.Specifically, more pathways showed significant enrichment in the fat and liver than in other tissues, while no pathway was enriched in the muscle.Conclusions: This study identified a total of 74863 nonredundant RNA editing sites in seven tissues and revealed the potential importance of RNA editing in tissue function. Our findings largely extend the porcine editome and enhance our understanding of RNA editing in swine.
Background: RNA editing is a co/posttranscriptional modification mechanism that increases the diversity of transcripts, with potential functional consequences. The advent of next-generation sequencing technologies has enabled the identification of RNA edits at unprecedented throughput and resolution. However, our knowledge of RNA editing in swine is still limited.Results: Here, we utilized RES-Scanner to identify RNA editing sites in the brain, subcutaneous fat, heart, liver,muscle, lung and ovary in three 180-day-old Large White gilts based on matched strand-specific RNA sequencing and whole-genome resequencing datasets. In total, we identified 74863 editing sites, and 92.1% of these sites caused adenosine-to-guanosine(A-to-G) conversion. Most A-to-G sites were located in noncoding regions and generally had low editing levels. In total, 151 A-to-G sites were detected in coding regions(CDS), including 94 sites that could lead to nonsynonymous amino acid changes. We provide further evidence supporting a previous observation that pig transcriptomes are highly editable at PRE-1 elements. The number of A-to-G editing sites ranged from 4155(muscle) to 25001(brain) across the seven tissues. The expression levels of the ADAR enzymes could explain some but not all of this variation across tissues. The functional analysis of the genes with tissuespecific editing sites in each tissue revealed that RNA editing might play important roles in tissue function.Specifically, more pathways showed significant enrichment in the fat and liver than in other tissues, while no pathway was enriched in the muscle.Conclusions: This study identified a total of 74863 nonredundant RNA editing sites in seven tissues and revealed the potential importance of RNA editing in tissue function. Our findings largely extend the porcine editome and enhance our understanding of RNA editing in swine.
引文
1.Benne R,Van Den Burg J,Brakenhoff JP,Sloof P,Van Boom JH,Tromp MC.Major transcript of the frameshifted coxll gene from trypanosome mitochondria contains four nucleotides that are not encoded in the DNA.Cell.1986;46:819-26.
2.Farajollahi S,Maas S.Molecular diversity through RNA editing:a balancing act.Trends Genet.2010;26:221-30.
3.Tajaddod M,Jantsch MF,Licht K.The dynamic epitranscriptome:a to Iediting modulates genetic information.Chromosoma.2016;125:51-63.
4.Nishikura K.A-to-I editing of coding and non-coding RNAs by ADARs.Nat Rev Mol Cell Biol.2016;17:83-96.
5.Chen J,Peng Z,Zhang R,Yang X,Tan BC,Fang H,et al.RNA editome in rhesus macaque shaped by purifying selection.PLoS Genet.2014;10:e1004274.
6.Peng Z,Cheng Y,Tan BC-M,Kang L,Tian Z,Zhu Y,et al.Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome.Nat Biotechnol.2012;30:253-60.
7.Valente L,Nishikura K.ADAR gene family and A-to-I RNA editing:diverse roles in posttranscriptional gene regulation.Prog Nucleic Acid Res Mol Biol.2005;79:299-338.
8.Higuchi M,Maas S,Single FN,Hartner J,Rozov A,Burnashev N,et al.Point mutation in an AMPA receptor gene rescues lethality in mice deficientin the RNA-editing enzyme ADAR2.Nature.2000;406:78-81.
9.Wang Q,Khillan J,Gadue P,Nishikura K.Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis.Science.2000;290:1765-8.
10.Brennicke A,Marchfelder A,Binder S.RNA editing.FEMS Microbiol Rev.1999;23:297-316.
11.Wang Y,Xu X,Yu S,Jeong KJ,Zhou Z,Han L,et al.Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers.Genome Res.2017;27:1112-25.
12.Wang C,Zou J,Ma X,Wang E,Peng G.Mechanisms and implications of ADAR-mediated RNA editing in cancer.Cancer Lett.2017;411:27-34.
13.Tan MH,Li Q,Shanmugam R,Piskol R,Kohler J,Young AN,et al.Dynamic landscape and regulation of RNA editing in mammals.Nature.2017;550:249-54.
14.Picardi E,Manzari C,Mastropasqua F,Aiello I,D’Erchia AM,Pesole G.Profiling RNA editing in human tissues:towards the inosinome atlas.Sci Rep.2015;5:14941.
15.Blanc V,Park E,Schaefer S,Miller M,Lin Y,Kennedy S,et al.Genome-wide identification and functional analysis of Apobec-1-mediated C-to-U RNAediting in mouse small intestine and liver.Genome Biol.2014;15:R79.
16.Lagarrigue S,Hormozdiari F,Martin LJ,Lecerf F,Hasin Y,Rau C,et al.Limited RNA editing in exons of mouse liver and adipose.Genetics.2013;193:1107-15.
17.Gu T,Buaas FW,Simons AK,Ackert-Bicknell CL,Braun RE,Hibbs MA.Canonical A-to-I and C-to-U RNA editing is enriched at 3'UTRs and microRNA target sites in multiple mouse tissues.PLoS One.2012;7:e33720.
18.Danecek P,Nellaker C,McIntyre RE,Buendia-Buendia JE,Bumpstead S,Ponting CP,et al.High levels of RNA-editing site conservation amongst 15laboratory mouse strains.Genome Biol.2012;13:26.
19.Li M,Wang IX,Li Y,Bruzel A,Richards AL,Toung JM,et al.Widespread RNAand DNA sequence differences in the human transcriptome.Science.2011;333:53-8.
20.Paz N,Levanon EY,Amariglio N,Heimberger AB,Ram Z,Constantini S,et al.Altered adenosine-to-inosine RNA editing in human cancer.Genome Res.2007;17:1586-95.
21.Gallo A,Locatelli F.ADARs:allies or enemies?The importance of A-to-I RNAediting in human disease:from cancer to HIV-1.Biol Rev.2012;87:95-110.
22.Funkhouser SA,Steibel JP,Bates RO,Raney NE,Schenk D,Ernst CW.Evidence for transcriptome-wide RNA editing among Sus scrofa PRE-1 SINEelements.BMC Genomics.2017;18:360.
23.Wang Z,Lian J,Li Q,Zhang P,Zhou Y,Zhan X,et al.RES-scanner:a software package for genome-wide identification of RNA-editing sites.GigaScience.2016;5:37.
24.Kim D,Pertea G,Trapnell C,Pimentel H,Kelley R,Salzberg SL.TopHat2:accurate alignment of transcriptomes in the presence of insertions,deletions and gene fusions.Genome Biol.2013;14:R36.
25.Anders S,Pyl PT,Huber W.HTSeq-a Python framework to work with highthroughput sequencing data.Bioinformatics.2015;31:166-169
26.Trapnell C,Williams BA,Pertea G,Mortazavi A,Kwan G,Van Baren MJ,et al.Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation.Nat Biotechnol.2010;28:511.
27.Yu G,Wang L,Han Y,He Q.clusterProfiler:an R package for comparing biological themes among gene clusters.OMICS:J Integrative Biol.2012;16:284-7.
28.Bakhtiarizadeh MR,Salehi A,Rivera RM.Genome-wide identification and analysis of A-to-I RNA editing events in bovine by transcriptome sequencing.PLoS One.2018;13:e0193316.
29.Wang K,Li M,Hakonarson H.ANNOVAR:functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res.2010;38:e164.
30.Lambert NJ,Gu SG,Zahler AM.The conformation of microRNA seed regions in native microRNPs is prearranged for presentation to mRNA targets.Nucleic Acids Res.2011;39:4827-35.
31.Betel D,Wilson M,Gabow A,Marks DS,Sander C.The microRNA.Org resource:targets and expression.Nucleic Acids Res.2008;36:D149-D53.
32.Cingolani P,Platts A,Wang LL,Coon M,Nguyen T,Wang L,et al.A program for annotating and predicting the effects of single nucleotide polymorphisms,SnpEff:SNPs in the genome of Drosophila melanogaster strain w1118;iso-2;iso-3.Fly.2012;6:80-92.
33.Goldberg L,Abutbul-Amitai M,Paret G,Nevo-Caspi Y.Alternative splicing of STAT3 is affected by RNA editing.DNA Cell Biol.2017;36:367-76.
34.Picardi E,Pesole G.REDItools:high-throughput RNA editing detection made easy.Bioinformatics.2013;29:1813-4.
35.Ramaswami G,Zhang R,Piskol R,Keegan LP,Deng P,O'connell MA,et al.Identifying RNA editing sites using RNA sequencing data alone.Nat Methods.2013;10:128.
36.Carmi S,Borukhov I,Levanon EY.Identification of widespread ultra-edited human RNAs.PLoS Genet.2011;7:e1002317.
37.Bass B,Hundley H,Li JB,Peng Z,Pickrell J,Xiao XG,et al.The difficult calls in RNA editing.Nat Biotechnol.2012;30:1207.
38.Bakhtiarizadeh MR,Shafiei H,Salehi A.Large-scale RNA editing profiling in different adult chicken tissues.bioRxiv.2018:319871.
39.Yu H,Wu Q,Zhang J,Zhang Y,Lu C,Cheng Y,et al.Genome-wide characterization of PRE-1 reveals a hidden evolutionary relationship between suidae and primates.BioRxiv.2015:025791.
40.Ramaswami G,Lin W,Piskol R,Tan MH,Davis C,Li JB.Accurate identification of human Alu and non-Alu RNA editing sites.Nat Methods.2012;9:579.
41.Porath HT,Carmi S,Levanon EY.A genome-wide map of hyper-edited RNAreveals numerous new sites.Nat Commun.2014;5:4726.
42.Bazak L,Haviv A,Barak M,Jacobhirsch J,Deng P,Zhang R,et al.A-to-I RNAediting occurs at over a hundred million genomic sites,located in a majority of human genes.Genome Res.2014;24:365.
43.Huntley MA,Lou M,Goldstein LD,Lawrence M,Dijkgraaf GJP,Kaminker JS,et al.Complex regulation of ADAR-mediated RNA-editing across tissues.BMC Genomics.2016;17:61.
44.Rodriguez J,Menet JS,Rosbash M.Nascent-seq indicates widespread cotranscriptional rna editing in drosophila.Mol Cell.2012;47:27-37.
45.Moran C.Molecular Genetics.In:F.Rothschild M,Ruvinsky A,editors.The genetics of the pig.UK:CABI;2011.p.73-100.
46.Ven?M,Bramsen JB,Bendixen C,Panitz F,Holm I,?hman M,et al.Spatiotemporal regulation of ADAR editing during development in porcine neural tissues.RNA Biol.2012;9:1054-65.
47.K?hler M,Burnashev N,Sakmann B,Seeburg PH.Determinants of Ca2+permeability in both TM1 and TM2 of high affinity kainate receptor channels:diversity by RNA editing.Neuron.1993;10:491-500.
48.Chan THM,Lin CH,Qi L,Fei J,Li Y,Yong KJ,et al.A disrupted RNA editing balance mediated by ADARs(adenosine DeAminases that act on RNA)in human hepatocellular carcinoma.Gut.2014;63:832-43.
49.Gonzalez C,Lopez-Rodriguez A,Srikumar D,Rosenthal JJ,Holmgren M.Editing of human K V 1.1 channel mRNAs disrupts binding of the N-terminus tip at the intracellular cavity.Nat Commun.2011;2:436.
50.Lomeli H,Mosbacher J,Melcher T,Hoger T,Kuner T,Monyer H,et al.Control of kinetic properties of AMPA receptor channels by nuclear RNAediting.Science.1994;266:1709-13.
51.Burns CM,Chu H,Rueter SM,Hutchinson LK,Canton H,Sanders-Bush E,et al.Regulation of serotonin-2C receptor G-protein coupling by RNAediting.Nature.1997;387:303.
52.Brawand D,Soumillon M,Necsulea A,Julien P,Csárdi G,Harrigan P,et al.The evolution of gene expression levels in mammalian organs.Nature.2011;478:343.
53.Shin Y,H-j J,Jung M,Yoo S,Subramaniyam S,Markkandan K,et al.Discovery of gene sources for economic traits in Hanwoo by wholegenome resequencing.Asian Australas J Anim Sci.2016;29:1353.
54.Yu H,Zhang M,Ma Y,Lu J,Pan J,Pan P,et al.5-ALA ameliorates hepatic steatosis through AMPK signaling pathway.J Mol Endocrinol.2017;59:121-8.
55.Watt MJ,Holmes AG,Pinnamaneni SK,Garnham AP,Steinberg GR,Kemp BE,et al.Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue.American Journal of Physiology-Endocrinology and Metabolism.2006;290:E500-E8.
56.Ahmadian M,Abbott MJ,Tang T,Hudak CS,Kim Y,Bruss M,et al.Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype.Cell Metab.2011;13:739-48.
57.Frayn KN,Arner P,Ykij?rvinen H.Fatty acid metabolism in adipose tissue,muscle and liver in health and disease.Essays Biochem.2006;42:89.
58.Nishikura K.Functions and regulation of RNA editing by ADAR deaminases.Annu Rev Biochem.2010;79:321-49.
59.Oakes E,Anderson A,Cohen-Gadol A,Hundley HA.Adenosine deaminase that acts on RNA 3(ADAR3)binding to glutamate receptor subunit B premRNA inhibits RNA editing in glioblastoma.J Biol Chem.2017;292:4326.
2.Farajollahi S,Maas S.Molecular diversity through RNA editing:a balancing act.Trends Genet.2010;26:221-30.
3.Tajaddod M,Jantsch MF,Licht K.The dynamic epitranscriptome:a to Iediting modulates genetic information.Chromosoma.2016;125:51-63.
4.Nishikura K.A-to-I editing of coding and non-coding RNAs by ADARs.Nat Rev Mol Cell Biol.2016;17:83-96.
5.Chen J,Peng Z,Zhang R,Yang X,Tan BC,Fang H,et al.RNA editome in rhesus macaque shaped by purifying selection.PLoS Genet.2014;10:e1004274.
6.Peng Z,Cheng Y,Tan BC-M,Kang L,Tian Z,Zhu Y,et al.Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome.Nat Biotechnol.2012;30:253-60.
7.Valente L,Nishikura K.ADAR gene family and A-to-I RNA editing:diverse roles in posttranscriptional gene regulation.Prog Nucleic Acid Res Mol Biol.2005;79:299-338.
8.Higuchi M,Maas S,Single FN,Hartner J,Rozov A,Burnashev N,et al.Point mutation in an AMPA receptor gene rescues lethality in mice deficientin the RNA-editing enzyme ADAR2.Nature.2000;406:78-81.
9.Wang Q,Khillan J,Gadue P,Nishikura K.Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis.Science.2000;290:1765-8.
10.Brennicke A,Marchfelder A,Binder S.RNA editing.FEMS Microbiol Rev.1999;23:297-316.
11.Wang Y,Xu X,Yu S,Jeong KJ,Zhou Z,Han L,et al.Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers.Genome Res.2017;27:1112-25.
12.Wang C,Zou J,Ma X,Wang E,Peng G.Mechanisms and implications of ADAR-mediated RNA editing in cancer.Cancer Lett.2017;411:27-34.
13.Tan MH,Li Q,Shanmugam R,Piskol R,Kohler J,Young AN,et al.Dynamic landscape and regulation of RNA editing in mammals.Nature.2017;550:249-54.
14.Picardi E,Manzari C,Mastropasqua F,Aiello I,D’Erchia AM,Pesole G.Profiling RNA editing in human tissues:towards the inosinome atlas.Sci Rep.2015;5:14941.
15.Blanc V,Park E,Schaefer S,Miller M,Lin Y,Kennedy S,et al.Genome-wide identification and functional analysis of Apobec-1-mediated C-to-U RNAediting in mouse small intestine and liver.Genome Biol.2014;15:R79.
16.Lagarrigue S,Hormozdiari F,Martin LJ,Lecerf F,Hasin Y,Rau C,et al.Limited RNA editing in exons of mouse liver and adipose.Genetics.2013;193:1107-15.
17.Gu T,Buaas FW,Simons AK,Ackert-Bicknell CL,Braun RE,Hibbs MA.Canonical A-to-I and C-to-U RNA editing is enriched at 3'UTRs and microRNA target sites in multiple mouse tissues.PLoS One.2012;7:e33720.
18.Danecek P,Nellaker C,McIntyre RE,Buendia-Buendia JE,Bumpstead S,Ponting CP,et al.High levels of RNA-editing site conservation amongst 15laboratory mouse strains.Genome Biol.2012;13:26.
19.Li M,Wang IX,Li Y,Bruzel A,Richards AL,Toung JM,et al.Widespread RNAand DNA sequence differences in the human transcriptome.Science.2011;333:53-8.
20.Paz N,Levanon EY,Amariglio N,Heimberger AB,Ram Z,Constantini S,et al.Altered adenosine-to-inosine RNA editing in human cancer.Genome Res.2007;17:1586-95.
21.Gallo A,Locatelli F.ADARs:allies or enemies?The importance of A-to-I RNAediting in human disease:from cancer to HIV-1.Biol Rev.2012;87:95-110.
22.Funkhouser SA,Steibel JP,Bates RO,Raney NE,Schenk D,Ernst CW.Evidence for transcriptome-wide RNA editing among Sus scrofa PRE-1 SINEelements.BMC Genomics.2017;18:360.
23.Wang Z,Lian J,Li Q,Zhang P,Zhou Y,Zhan X,et al.RES-scanner:a software package for genome-wide identification of RNA-editing sites.GigaScience.2016;5:37.
24.Kim D,Pertea G,Trapnell C,Pimentel H,Kelley R,Salzberg SL.TopHat2:accurate alignment of transcriptomes in the presence of insertions,deletions and gene fusions.Genome Biol.2013;14:R36.
25.Anders S,Pyl PT,Huber W.HTSeq-a Python framework to work with highthroughput sequencing data.Bioinformatics.2015;31:166-169
26.Trapnell C,Williams BA,Pertea G,Mortazavi A,Kwan G,Van Baren MJ,et al.Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation.Nat Biotechnol.2010;28:511.
27.Yu G,Wang L,Han Y,He Q.clusterProfiler:an R package for comparing biological themes among gene clusters.OMICS:J Integrative Biol.2012;16:284-7.
28.Bakhtiarizadeh MR,Salehi A,Rivera RM.Genome-wide identification and analysis of A-to-I RNA editing events in bovine by transcriptome sequencing.PLoS One.2018;13:e0193316.
29.Wang K,Li M,Hakonarson H.ANNOVAR:functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res.2010;38:e164.
30.Lambert NJ,Gu SG,Zahler AM.The conformation of microRNA seed regions in native microRNPs is prearranged for presentation to mRNA targets.Nucleic Acids Res.2011;39:4827-35.
31.Betel D,Wilson M,Gabow A,Marks DS,Sander C.The microRNA.Org resource:targets and expression.Nucleic Acids Res.2008;36:D149-D53.
32.Cingolani P,Platts A,Wang LL,Coon M,Nguyen T,Wang L,et al.A program for annotating and predicting the effects of single nucleotide polymorphisms,SnpEff:SNPs in the genome of Drosophila melanogaster strain w1118;iso-2;iso-3.Fly.2012;6:80-92.
33.Goldberg L,Abutbul-Amitai M,Paret G,Nevo-Caspi Y.Alternative splicing of STAT3 is affected by RNA editing.DNA Cell Biol.2017;36:367-76.
34.Picardi E,Pesole G.REDItools:high-throughput RNA editing detection made easy.Bioinformatics.2013;29:1813-4.
35.Ramaswami G,Zhang R,Piskol R,Keegan LP,Deng P,O'connell MA,et al.Identifying RNA editing sites using RNA sequencing data alone.Nat Methods.2013;10:128.
36.Carmi S,Borukhov I,Levanon EY.Identification of widespread ultra-edited human RNAs.PLoS Genet.2011;7:e1002317.
37.Bass B,Hundley H,Li JB,Peng Z,Pickrell J,Xiao XG,et al.The difficult calls in RNA editing.Nat Biotechnol.2012;30:1207.
38.Bakhtiarizadeh MR,Shafiei H,Salehi A.Large-scale RNA editing profiling in different adult chicken tissues.bioRxiv.2018:319871.
39.Yu H,Wu Q,Zhang J,Zhang Y,Lu C,Cheng Y,et al.Genome-wide characterization of PRE-1 reveals a hidden evolutionary relationship between suidae and primates.BioRxiv.2015:025791.
40.Ramaswami G,Lin W,Piskol R,Tan MH,Davis C,Li JB.Accurate identification of human Alu and non-Alu RNA editing sites.Nat Methods.2012;9:579.
41.Porath HT,Carmi S,Levanon EY.A genome-wide map of hyper-edited RNAreveals numerous new sites.Nat Commun.2014;5:4726.
42.Bazak L,Haviv A,Barak M,Jacobhirsch J,Deng P,Zhang R,et al.A-to-I RNAediting occurs at over a hundred million genomic sites,located in a majority of human genes.Genome Res.2014;24:365.
43.Huntley MA,Lou M,Goldstein LD,Lawrence M,Dijkgraaf GJP,Kaminker JS,et al.Complex regulation of ADAR-mediated RNA-editing across tissues.BMC Genomics.2016;17:61.
44.Rodriguez J,Menet JS,Rosbash M.Nascent-seq indicates widespread cotranscriptional rna editing in drosophila.Mol Cell.2012;47:27-37.
45.Moran C.Molecular Genetics.In:F.Rothschild M,Ruvinsky A,editors.The genetics of the pig.UK:CABI;2011.p.73-100.
46.Ven?M,Bramsen JB,Bendixen C,Panitz F,Holm I,?hman M,et al.Spatiotemporal regulation of ADAR editing during development in porcine neural tissues.RNA Biol.2012;9:1054-65.
47.K?hler M,Burnashev N,Sakmann B,Seeburg PH.Determinants of Ca2+permeability in both TM1 and TM2 of high affinity kainate receptor channels:diversity by RNA editing.Neuron.1993;10:491-500.
48.Chan THM,Lin CH,Qi L,Fei J,Li Y,Yong KJ,et al.A disrupted RNA editing balance mediated by ADARs(adenosine DeAminases that act on RNA)in human hepatocellular carcinoma.Gut.2014;63:832-43.
49.Gonzalez C,Lopez-Rodriguez A,Srikumar D,Rosenthal JJ,Holmgren M.Editing of human K V 1.1 channel mRNAs disrupts binding of the N-terminus tip at the intracellular cavity.Nat Commun.2011;2:436.
50.Lomeli H,Mosbacher J,Melcher T,Hoger T,Kuner T,Monyer H,et al.Control of kinetic properties of AMPA receptor channels by nuclear RNAediting.Science.1994;266:1709-13.
51.Burns CM,Chu H,Rueter SM,Hutchinson LK,Canton H,Sanders-Bush E,et al.Regulation of serotonin-2C receptor G-protein coupling by RNAediting.Nature.1997;387:303.
52.Brawand D,Soumillon M,Necsulea A,Julien P,Csárdi G,Harrigan P,et al.The evolution of gene expression levels in mammalian organs.Nature.2011;478:343.
53.Shin Y,H-j J,Jung M,Yoo S,Subramaniyam S,Markkandan K,et al.Discovery of gene sources for economic traits in Hanwoo by wholegenome resequencing.Asian Australas J Anim Sci.2016;29:1353.
54.Yu H,Zhang M,Ma Y,Lu J,Pan J,Pan P,et al.5-ALA ameliorates hepatic steatosis through AMPK signaling pathway.J Mol Endocrinol.2017;59:121-8.
55.Watt MJ,Holmes AG,Pinnamaneni SK,Garnham AP,Steinberg GR,Kemp BE,et al.Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue.American Journal of Physiology-Endocrinology and Metabolism.2006;290:E500-E8.
56.Ahmadian M,Abbott MJ,Tang T,Hudak CS,Kim Y,Bruss M,et al.Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype.Cell Metab.2011;13:739-48.
57.Frayn KN,Arner P,Ykij?rvinen H.Fatty acid metabolism in adipose tissue,muscle and liver in health and disease.Essays Biochem.2006;42:89.
58.Nishikura K.Functions and regulation of RNA editing by ADAR deaminases.Annu Rev Biochem.2010;79:321-49.
59.Oakes E,Anderson A,Cohen-Gadol A,Hundley HA.Adenosine deaminase that acts on RNA 3(ADAR3)binding to glutamate receptor subunit B premRNA inhibits RNA editing in glioblastoma.J Biol Chem.2017;292:4326.