DNA甲基化与去甲基化调控脂肪沉积的研究进展
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摘要
脂肪沉积是一个复杂的生物学过程,受遗传和表观遗传的调控作用。DNA甲基化和去甲基化是表观遗传修饰的重要方式,可通过与转录因子的相互作用或改变染色质的结构调控基因的表达,进而参与机体生长发育和细胞分化等重要的生命过程。动物脂肪沉积是脂肪细胞增殖分化和肥大的结果,脂肪细胞分化是由多能干细胞经前体脂肪细胞向成熟脂肪细胞转化的过程。相关研究表明,转录因子过氧化物酶体增殖物激活受体γ(peroxi-some proliferator activiated receptorγ,PPARγ)和CCAAT增强子结合蛋白家族(CCAAT enchancer binding proteinfamily,CEBPs)在脂肪沉积过程中起关键调控作用。近期研究发现,DNA甲基化可以通过调控脂肪形成过程中相关基因的表达而参与脂肪细胞的分化和脂肪组织的生长发育。去甲基化也可影响动物脂肪沉积过程,但其具体机制目前尚不清楚。作者主要介绍了DNA甲基化和去甲基化的定义、发生位点、生物学功能、参与DNA甲基化和去甲基化过程中的酶及其作用机制,概述了脂肪沉积过程及PPARγ、C/EBPα等转录因子在脂肪沉积过程中的调控作用,重点阐述了DNA甲基化和去甲基化对脂肪形成相关基因的表达和对脂肪细胞分化的影响,旨在为阐明脂肪沉积机制及改善动物肉质品质提供参考。
Adipose deposition is a complex biological process,and is regulated by genetic and epigenetic effects.DNA methylation and demethylation are important ways of epigenetic modification,can participate in important life processes such as growth and development of body and cell differentiation by interacting with transcription factors or altering the structure of chromatin.Animal adipose deposition is the result of adipocyte proliferation and differentiation and hypertrophy.Adipocyte differentiation is a process in which pluripotent stem cells are transformed into precursor adipocyte and then differentiated into mature adipocytes.Related studies have shownthat the transcription factor peroxisome proliferator activiated receptorγ(PPARγ)and CCAAT enhancer binding protein family(CEBPs)play key regulatory roles in adipose deposition.Recent studies found that DNA methylation can participate in the differentiation of adipocytes and the growth and development of adipose tissue by regulating the expression of related genes in the process of adipogenesis.Demethylation can also affect the adipose deposition process in animals,but the specific mechanism is still unclear.This article introduced the definition,site of occurrence biological function,related enzyme and mechanism of DNA methylation and demethylation,then introduced the adipose deposition process and the role of transcriptional regulators such as PPARγand C/EBPαin adipose deposition.The effects of DNA methylation and demethylation on the expression of genes involved in adipogenesis and adipocytes differentiation were highlighted.This paper provides a reference for clarifying the mechanism of adipose deposition and improving meat quality in animal production.
Adipose deposition is a complex biological process,and is regulated by genetic and epigenetic effects.DNA methylation and demethylation are important ways of epigenetic modification,can participate in important life processes such as growth and development of body and cell differentiation by interacting with transcription factors or altering the structure of chromatin.Animal adipose deposition is the result of adipocyte proliferation and differentiation and hypertrophy.Adipocyte differentiation is a process in which pluripotent stem cells are transformed into precursor adipocyte and then differentiated into mature adipocytes.Related studies have shownthat the transcription factor peroxisome proliferator activiated receptorγ(PPARγ)and CCAAT enhancer binding protein family(CEBPs)play key regulatory roles in adipose deposition.Recent studies found that DNA methylation can participate in the differentiation of adipocytes and the growth and development of adipose tissue by regulating the expression of related genes in the process of adipogenesis.Demethylation can also affect the adipose deposition process in animals,but the specific mechanism is still unclear.This article introduced the definition,site of occurrence biological function,related enzyme and mechanism of DNA methylation and demethylation,then introduced the adipose deposition process and the role of transcriptional regulators such as PPARγand C/EBPαin adipose deposition.The effects of DNA methylation and demethylation on the expression of genes involved in adipogenesis and adipocytes differentiation were highlighted.This paper provides a reference for clarifying the mechanism of adipose deposition and improving meat quality in animal production.
引文
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[14]KULIS M,QUEIR S A C,BEEKMAN R,et al.Intragenic DNA methylation in transcriptional regulation,normal differentiation and cancer[J].Biochimica et Biophysica Acta(BBA)-Gene Regulatory Mechanisms,2013,1829(11):1161-1174.
[15]SCH BELER D.ESCI award lecture:Regulation,function and biomarker potential of DNA methylation[J].European Journal of Clinical Investigation,2015,45(3):288-293.
[16]HERMAN J G,BAYLIN S B.Gene silencing in cancer in association with promoter hypermethylation[J].New England Journal of Medicine,2003,349(21):2042-2054.
[17]ZHU J K.Active DNA demethylation mediated by DNA glycosylases[J].Annual Review of Genetics,2009,43(1):143-166.
[18]ITO S,SHEN L,DAI Q,et al.Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine[J].Science,2011,333(6047):1300-1303.
[19]LLUIS F,COSMA M P.Resetting epigenetic signatures to induce somatic cell reprogramming[J].Cellular&Molecular Life Sciences CMLS,2013,70(8):1413-1424.
[20]GU T P,GUO F,YANG H,et al.The role of Tet3DNA dioxygenase in epigenetic reprogramming by oocytes[J].Nature,2011,477(7366):606-610.
[21]SEISENBERGER S,REIK W.Reprogramming DNAmethylation in the mammalian life cycle:Building and breaking epigenetic barriers[J].Philosophical Transactions of the Royal Society B:Biological Sciences,2013,368(1609):20110330.
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[25]BHATTACHARYA SK R S,CERVONI N,SZYF M.Amammalian protein with specicdemethylase activity for mCpG DNA[J].Nature,1999,397(6720):579-583.
[26]LIUTKEVICIUTE Z,LUKINAVICIUS G,MA-SEVICIUS V,et al.Cytosine-5-methyltransferases add aldehydes to DNA[J].Nature Chemical Biology,2009,5(6):400-402.
[27]VALINLUCK V,SOWERS L C.Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1[J].Cancer Research,2007,67(3):946-950.
[28]QI Q T,LANE M D.Adipogenesis:From stem cell to adipocyte[J].Annual Review of Biochemistry,2012,81(81):715-736.
[29]HAUSMAN D B,DIGIROLAMO M,BARTNESS T J,et al.The biology of white adipocyte proliferation[J].Obesity Reviews,2001,2(4):239-254.
[30]LEE Y H,MOTTILLO E P,GRANNEMAN J G.Adipose tissue plasticity from WAT to BAT and in between[J].Biochimica et Biophysica Acta,2014,1842(3):358-369.
[31]RODRIGUE Z A,ELABD C,DELTEIL F,et al.Adipocyte differentiation of multipotent cells established from human adipose tissue[J].Biochemical&Biophysical Research Communications,2004,315(2):255-263.
[32]SIERSB K R,NIELSEN R,MANDRUP S.Transcriptional networks and chromatin remodeling controlling adipogenesis[J].Trends in Endocrinology and Metabolism:TEM,2012,23(2):56-64.
[33]TANG Q Q,ZHANG J W,DANIEL L M.Sequential gene promoter interactions by C/EBPbeta,C/EBPalpha,and PPARgamma during adipogenesis[J].Biochemical&Biophysical Research Communications,2004,319(1):235-239.
[34]CUI T T,XING T Y,CHU Y K,et al.Genetic and epigenetic regulation of PPARγduring adipogenesis[J].Hereditas,2017,39(11):1066-1077.
[35]ROSEN E D,SARRAF P,TROY A E,et al.PPARγis required for the differentiation of adipose tissue in vivo and in vitro[J].Molecular Cell,1999,4(4):611-617.
[36]YAN X,ZHU M J,DODSON M V,et al.Developmental programming of fetal skeletal muscle and adipose tissue development[J].Journal of Genomics,2013,1(1):29-38.
[37]FARMER S R.Transcriptional control of adipocyte formation[J].Cell Metabolism,2006,4(4):263-273.
[38]WU Z,ROSEN E D,BRUN R,et al.Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity[J].Molecular Cell,1999,3(2):151-158.
[39]PHAM T X,LEE J-Y.Epigenetic regulation of adipokines[J].International Journal of Molecular Sciences,2017,18(8):1740.
[40]LI M,WANG T,WU H,et al.Genome-wide DNAmethylation changes between the superficial and deep backfat tissues of the pig[J].International Journal of Molecular Sciences,2012,13(6):7098-7108.
[41]ZHOU Z Y,LI A,WANG L G,et al.DNA methylation signatures of long intergenic noncoding RNAs in porcine adipose and muscle tissues[J].Scientific Reports,2015,5:15435.
[42]BOWERS R R,KIM J W,OTTO T C,et al.Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation:Role of the BMP-4gene[J].Proceedings of the National Academy of Sciences of the United States of America,2006,103(35):13022-13027.
[43]FUJIKI K,KANO F,SHIOTA K,et al.Expression of the peroxisome proliferator activated receptorγgene is repressed by DNA methylation in visceral adipose tissue of mouse models of diabetes[J].BMC Biology,2009,7(1):38.
[44]LI H X,XIAO L,WANG C,et al.Review:Epigenetic regulation of adipocyte differentiation and adipogenesis[J].Journal of Zhejiang University-Science B,2010,11(10):784-791.
[45]BAIK M,VU T T T,PIAO M Y,et al.Association of DNA methylation levels with tissue-specific expression of adipogenic and lipogenic genes in longissimus dorsi muscle of Korean cattle[J].Asian-Australasian Journal of Animal Sciences,2014,27(10):1493-1498.
[46]SUN Y N.Epigenetic DNA methylation in the promoters of peroxisome proliferator-activated receptor in chicken lines divergently selected for fatness[J].Journal of Animal Science,2014,92(1):48-53.
[47]KAMSTRA J H,HRUBA E,BLUMBERG B,et al.Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47[J].Environmental Science&Technology,2014,48(7):4110-4119.
[48]MELZNER I,SCOTT V,DORSCH K,et al.Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoter[J].Journal of Biological Chemistry,2002,277(47):45420-45427.
[49]RUI W,JIN Z,ZHE G,et al.The methylation of C/EBPβgene promoter and regulated by GATA-2protein[J].Molecular Biology Reports,2013,40(2):797-801.
[50]KURODA M,TOMINAGA A,NAKAGAWA K,et al.DNA methylation suppresses leptin gene in 3T3-L1adipocytes[J].PLoS One,2016,11(8):e0160532.
[51]SHORE A,KARAMITRI A,KEMP P,et al.Role of Ucp1enhancer methylation and chromatin remodelling in the control of Ucp1expression in murine adipose tissue[J].Diabetologia,2010,53(6):1164-1173.
[52]LIANG X,YANG Q,FU X,et al.Maternal obesity epigenetically alters visceral fat progenitor cell properties in male offspring mice[J].Journal of Physiology,2016,594(15):4453-4466.
[53]YOO Y,PARK J H,WEIGEL C,et al.TET-mediated hydroxymethylcytosine at the PPARγlocus is required for initiation of adipogenic differentiation[J].International Journal of Obesity,2017,41(4):652-659.
[54]FUJIKI K,SHINODA A,KANO F,et al.PPARγ-induced parylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine[J].Nature Communications,2013,4:2262.
[55]ZHANG L J,ZHU Y N,GAO Y,et al.The MBD4gene plays an important role in porcine adipocyte differentiation[J].Cellular Physiology&Biochemistry International Journal of Experimental Cellular Physiology Biochemistry&Pharmacology,2014,34(4):1216-1226.
[56]ZHANG L J,LIU S Y,ZHU Y N,et al.Thymine DNA glycosylase gene knockdown can affect the differentiation of pig preadipocytes[J].Cellular Physiology&Biochemistry International Journal of Experimental Cellular Physiology Biochemistry&Pharmacology,2016,39(3):975-984.
[2]WU S C,ZHANG Y.Active DNA demethylation:Many roads lead to Rome[J].Nature Reviews Molecular Cell Biology,2010,11(9):607-620.
[3]CHEN H,KAZEMIER H G,DE GROOTE M L,et al.Induced DNA demethylation by targeting ten-eleven translocation 2 to the human ICAM-1promoter[J].Nucleic Acids Research,2014,42(3):1563-1574.
[4]ZHANG R,SHAO J,XIANG L.Gadd45aplays an essential role in active DNA demethylation during terminal osteogenic differentiation of adipose-derived mesenchymal stem cells[J].Journal of Biological Chemistry,2011,286(47):41083-41094.
[5]MOORE L D,LE T,FAN G.DNA methylation and its basic function[J].Neuropsychopharmacology Official Publication of the American College of Neuropsychopharmacology,2013,38(1):23-38.
[6]ALGIRE C,MEDRIKOVA D,HERZIG S.White and brown adipose stem cells:From signaling to clinical implications[J].Biochimica et Biophysica Acta,2013,1831(5):896-904.
[7]LI M,WU H,LUO Z,et al.An atlas of DNA methylomes in porcine adipose and muscle tissues[J].Nature Communications,2012,3:850.
[8]CUI D,XU X.DNA methyltransferases,DNA methylation,and age-associated cognitive function[J].International Journal of Molecular Sciences,2018,19(5):1315.
[9]SAKAMOTO H,KOGO Y,OHGANE J,et al.Sequential changes in genome-wide DNA methylation status during adipocyte differentiation[J].Biochemical&Biophysical Research Communications,2008,366(2):360-366.
[10]ITO S,D’ALESSIO A C,TARANOVA O V,et al.Role of Tet proteins in 5mC to 5hmC conversion,ES-cell self-renewal and inner cell mass specification[J].Nature,2010,466(7310):1129-1133.
[11]LI E,ZHANG Y.DNA Methylation in mammals[J].Cold Spring Harbor Perspectives in Biology,2014,6(5):a019133.
[12]CHEN T,LI E.Establishment and maintenance of DNA methylation patterns in mammals[J].Current Topics in Microbiology&Immunology,2006,301(12):179-201.
[13]CHENG X,BLUMENTHAL R M.Mammalian DNAmethyltransferases:A structural perspective[J].Structure,2008,16(3):341-350.
[14]KULIS M,QUEIR S A C,BEEKMAN R,et al.Intragenic DNA methylation in transcriptional regulation,normal differentiation and cancer[J].Biochimica et Biophysica Acta(BBA)-Gene Regulatory Mechanisms,2013,1829(11):1161-1174.
[15]SCH BELER D.ESCI award lecture:Regulation,function and biomarker potential of DNA methylation[J].European Journal of Clinical Investigation,2015,45(3):288-293.
[16]HERMAN J G,BAYLIN S B.Gene silencing in cancer in association with promoter hypermethylation[J].New England Journal of Medicine,2003,349(21):2042-2054.
[17]ZHU J K.Active DNA demethylation mediated by DNA glycosylases[J].Annual Review of Genetics,2009,43(1):143-166.
[18]ITO S,SHEN L,DAI Q,et al.Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine[J].Science,2011,333(6047):1300-1303.
[19]LLUIS F,COSMA M P.Resetting epigenetic signatures to induce somatic cell reprogramming[J].Cellular&Molecular Life Sciences CMLS,2013,70(8):1413-1424.
[20]GU T P,GUO F,YANG H,et al.The role of Tet3DNA dioxygenase in epigenetic reprogramming by oocytes[J].Nature,2011,477(7366):606-610.
[21]SEISENBERGER S,REIK W.Reprogramming DNAmethylation in the mammalian life cycle:Building and breaking epigenetic barriers[J].Philosophical Transactions of the Royal Society B:Biological Sciences,2013,368(1609):20110330.
[22]BING ZHU Y Z,HERBERT ANGLIKER,et al.5-Methylcytosine DNA glycosylase activity is also present in the human MBD4(GT mismatch glycosylase)and in a related avian sequence[J].Nucleic Acids Research,2000,28(21):4157-4165.
[23]SANCAR A,LINDSEY-BOLTZ L A,UNSAL-KAC-MAZ K,et al.Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints[J].Annual Review of Biochemistry,2004,73(1):39-85.
[24]TAHILIANI M,KOH K P,SHEN Y,et al.Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1[J].Science,2009,324(5929):930-935.
[25]BHATTACHARYA SK R S,CERVONI N,SZYF M.Amammalian protein with specicdemethylase activity for mCpG DNA[J].Nature,1999,397(6720):579-583.
[26]LIUTKEVICIUTE Z,LUKINAVICIUS G,MA-SEVICIUS V,et al.Cytosine-5-methyltransferases add aldehydes to DNA[J].Nature Chemical Biology,2009,5(6):400-402.
[27]VALINLUCK V,SOWERS L C.Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1[J].Cancer Research,2007,67(3):946-950.
[28]QI Q T,LANE M D.Adipogenesis:From stem cell to adipocyte[J].Annual Review of Biochemistry,2012,81(81):715-736.
[29]HAUSMAN D B,DIGIROLAMO M,BARTNESS T J,et al.The biology of white adipocyte proliferation[J].Obesity Reviews,2001,2(4):239-254.
[30]LEE Y H,MOTTILLO E P,GRANNEMAN J G.Adipose tissue plasticity from WAT to BAT and in between[J].Biochimica et Biophysica Acta,2014,1842(3):358-369.
[31]RODRIGUE Z A,ELABD C,DELTEIL F,et al.Adipocyte differentiation of multipotent cells established from human adipose tissue[J].Biochemical&Biophysical Research Communications,2004,315(2):255-263.
[32]SIERSB K R,NIELSEN R,MANDRUP S.Transcriptional networks and chromatin remodeling controlling adipogenesis[J].Trends in Endocrinology and Metabolism:TEM,2012,23(2):56-64.
[33]TANG Q Q,ZHANG J W,DANIEL L M.Sequential gene promoter interactions by C/EBPbeta,C/EBPalpha,and PPARgamma during adipogenesis[J].Biochemical&Biophysical Research Communications,2004,319(1):235-239.
[34]CUI T T,XING T Y,CHU Y K,et al.Genetic and epigenetic regulation of PPARγduring adipogenesis[J].Hereditas,2017,39(11):1066-1077.
[35]ROSEN E D,SARRAF P,TROY A E,et al.PPARγis required for the differentiation of adipose tissue in vivo and in vitro[J].Molecular Cell,1999,4(4):611-617.
[36]YAN X,ZHU M J,DODSON M V,et al.Developmental programming of fetal skeletal muscle and adipose tissue development[J].Journal of Genomics,2013,1(1):29-38.
[37]FARMER S R.Transcriptional control of adipocyte formation[J].Cell Metabolism,2006,4(4):263-273.
[38]WU Z,ROSEN E D,BRUN R,et al.Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity[J].Molecular Cell,1999,3(2):151-158.
[39]PHAM T X,LEE J-Y.Epigenetic regulation of adipokines[J].International Journal of Molecular Sciences,2017,18(8):1740.
[40]LI M,WANG T,WU H,et al.Genome-wide DNAmethylation changes between the superficial and deep backfat tissues of the pig[J].International Journal of Molecular Sciences,2012,13(6):7098-7108.
[41]ZHOU Z Y,LI A,WANG L G,et al.DNA methylation signatures of long intergenic noncoding RNAs in porcine adipose and muscle tissues[J].Scientific Reports,2015,5:15435.
[42]BOWERS R R,KIM J W,OTTO T C,et al.Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation:Role of the BMP-4gene[J].Proceedings of the National Academy of Sciences of the United States of America,2006,103(35):13022-13027.
[43]FUJIKI K,KANO F,SHIOTA K,et al.Expression of the peroxisome proliferator activated receptorγgene is repressed by DNA methylation in visceral adipose tissue of mouse models of diabetes[J].BMC Biology,2009,7(1):38.
[44]LI H X,XIAO L,WANG C,et al.Review:Epigenetic regulation of adipocyte differentiation and adipogenesis[J].Journal of Zhejiang University-Science B,2010,11(10):784-791.
[45]BAIK M,VU T T T,PIAO M Y,et al.Association of DNA methylation levels with tissue-specific expression of adipogenic and lipogenic genes in longissimus dorsi muscle of Korean cattle[J].Asian-Australasian Journal of Animal Sciences,2014,27(10):1493-1498.
[46]SUN Y N.Epigenetic DNA methylation in the promoters of peroxisome proliferator-activated receptor in chicken lines divergently selected for fatness[J].Journal of Animal Science,2014,92(1):48-53.
[47]KAMSTRA J H,HRUBA E,BLUMBERG B,et al.Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47[J].Environmental Science&Technology,2014,48(7):4110-4119.
[48]MELZNER I,SCOTT V,DORSCH K,et al.Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoter[J].Journal of Biological Chemistry,2002,277(47):45420-45427.
[49]RUI W,JIN Z,ZHE G,et al.The methylation of C/EBPβgene promoter and regulated by GATA-2protein[J].Molecular Biology Reports,2013,40(2):797-801.
[50]KURODA M,TOMINAGA A,NAKAGAWA K,et al.DNA methylation suppresses leptin gene in 3T3-L1adipocytes[J].PLoS One,2016,11(8):e0160532.
[51]SHORE A,KARAMITRI A,KEMP P,et al.Role of Ucp1enhancer methylation and chromatin remodelling in the control of Ucp1expression in murine adipose tissue[J].Diabetologia,2010,53(6):1164-1173.
[52]LIANG X,YANG Q,FU X,et al.Maternal obesity epigenetically alters visceral fat progenitor cell properties in male offspring mice[J].Journal of Physiology,2016,594(15):4453-4466.
[53]YOO Y,PARK J H,WEIGEL C,et al.TET-mediated hydroxymethylcytosine at the PPARγlocus is required for initiation of adipogenic differentiation[J].International Journal of Obesity,2017,41(4):652-659.
[54]FUJIKI K,SHINODA A,KANO F,et al.PPARγ-induced parylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine[J].Nature Communications,2013,4:2262.
[55]ZHANG L J,ZHU Y N,GAO Y,et al.The MBD4gene plays an important role in porcine adipocyte differentiation[J].Cellular Physiology&Biochemistry International Journal of Experimental Cellular Physiology Biochemistry&Pharmacology,2014,34(4):1216-1226.
[56]ZHANG L J,LIU S Y,ZHU Y N,et al.Thymine DNA glycosylase gene knockdown can affect the differentiation of pig preadipocytes[J].Cellular Physiology&Biochemistry International Journal of Experimental Cellular Physiology Biochemistry&Pharmacology,2016,39(3):975-984.
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