You might find this additional
137 articles, 34 of which you can access for free at:
This article cites /content/109/2/586.full#ref-list-1 2 other HighWire-hosted articles: This article has been cited by
/content/109/2/586#cited-by including high resolution figures, can be found at:
Updated information and rvices /content/109/2/586.full can be found at:
Journal of Applied Physiology about Additional material and information /publications/jappl This information is current as of April 10, 2013.
© 2010 the American Physiological Society. ISSN: 8750-7587, ESSN: 1522-1601. Visit our website a
t year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright physiology, especially tho papers emphasizing adaptive and integrative mechanisms. It is published 12 times a publishes original papers that deal with diver area of rearch in applied Journal of Applied Physiology at South Univ of Sci and Tech of China on April 10, 2013
/Downloaded from
HIGHLIGHTED TOPIC Epigenetics in Health and Dia
Epigenetic alterations in aging
Susana Gonzalo
Radiation and Cancer Biology Division,Department of Radiation Oncology,and Department of Cell Biology and Physiology, Washington University School of Medicine,St.Louis,Missouri
Submitted4March2010;accepted infinal form3May2010
Gonzalo S.Epigenetic alterations in aging.J Appl Physiol109:586–597,2010.
First published May6,2010;doi:10.1152/japplphysiol.00238.2010.—Aging is a
multifaceted process characterized by genetic and epigenetic changes in the
genome.The genetic component of aging received initially all of the attention.
Telomere attrition and accumulation of mutations due to a progressive deficiency in
the repair of DNA damage with age remain leading caus of genomic instability.
However,epigenetic mechanisms have now emerged as key contributors to the
alterations of genome structure and function that accompany aging.The three
pillars of epigenetic regulation are DNA methylation,histone modifications,and
noncoding RNA species.Alterations of the epigenetic mechanisms affect the vast
majority of nuclear process,including gene transcription and silencing,DNA
replication and repair,cell cycle progression,and telomere and centromere struc-
ture and function.Here,we summarize the lines of evidence indicating that the
epigenetic defects might reprent a major factor in the pathophysiology of aging
and aging-related dias,especially cancer.
cancer;epigenetic changes
A NEW CONSENSUS FOR THE DEFINITION of epigenetics has recently been reached:“An epigenetic trait is a stably heritable pheno-type resulting from changes in a chromosome without alter-ations in the DNA quence”(8).A cascade of signaling events,activated by an environmental cue referred to as“epi-genator”,is required to effect the chromosomal changes. Next,an“epigenetic initiator”establishes the region of the chromosome that will undergo epigenetic regulation,and an “epigenetic maintainer”executes the epigenetic modifications that change chromatin structure(8).The main players that orchestrate chromatin regulation are DNA methylation,histone modifications,and RNA species.Extensive cross talk among the players regulates gene expression and maintains faculta-tive and constitutive heterochromatin.Establishment of differ-ent combinations of chromatin marks ts codes that can be read by chromatin-associating complexes(58,59,66,118). The complexes,in turn,execute additional chromatin mod-ifications and/or recruit effectors that regulate th
e specific biological process:transcription,DNA replication and repair, cell division,and centromere and telomere function,among others(7,9,15,46,103).Compelling evidence indicates that the combination of genetic and epigenetic alterations contributes to human dia,including neurological and cardiovascular dis-eas,autoimmune disorders,cancer,and aging.Genetic alter-ations,such as mutations,deletions,and translocations or telomere loss,are among the leading caus of genomic instability in aging and cancer.A whole body of evidence indicates that epigenetic alterations also contribute to aging-associated pathologies,espe-cially cancer.Epigenetic changes may initiate aging and cancer phenotypes,or prime cells,in such a way as to make them more susceptible to subquent genetic or epigenetic alterations.The accumulation of further genetic or epigenetic changes over time would promote the progression of aging and cancer phenotypes (Fig.1).
EPIGENETIC MECHANISMS:DNA METHYLATION,HISTONE MODIFICATIONS,AND NONCODING RNAs
The basic unit of chromatin,the nucleosome,consists of DNA that wraps around an octamer of histones(78)(Fig.2A). Many different cellular activities target the nucleosome as to modulate chromatin structure,either at specific genomic loci, or at large chromosomal domains(115).The histon
e tails protrude from the nucleosome core and are subjected to dif-ferent posttranslational modifications(59).An extremely com-plicated picture has emerged about the types of posttransla-tional modifications of histones and the enzymatic activities responsible for the modifications(64,66,83).Histone mod-ifications include rine and threonine phosphorylation,lysine acetylation,lysine and arginine methylation,ADP-ribosylation of glutamic acids,lysine sumoylation and ubiquitylation,and proline isomerization(Fig.2B).The main purpo of the histone modifications is to prent a platform for binding of a variety of chromatin associating/remodeling activities that,in turn,allow or restrict the access of regulatory proteins to DNA.
Address for reprint requests and other correspondence:S.Gonzalo,Radia-tion and Cancer Biology Division,Dept.of Radiation Oncology,Washington Univ.School of Medicine,4511Forest Park,St.Louis,MO63108(e-mail: sgonzalo@radonc.wustl.edu).
J Appl Physiol109:586–597,2010. First published May6,2010;doi:10.1152/japplphysiol.00238.2010.
Review
at South Univ of Sci and Tech of China on April 10, 2013/
Downloaded from
Methylation of nucleosomal DNA by DNA methyltrans-fera activities (DNMTs)is established as a means to modu-毕业和结业
late the transcriptional activation or repression of many genes.DNA methylation consists of the addition of a methyl group to the cytosine of the CpG dinucleotide.CpGs are found at low frequency in the genome,but accumulate at specific gene promoters,CpG islands (11,65).The bulk of DNA methyl-ation is found at repetitive quences,such as transposons and pericentric and subtelomeric chromatin.Methylation of repet-itive quences prevents recombination or translocation throughout the genome (20).The types of posttranslational modifications of histones and the degree of DNA methylation determine a specific chromatin structure (71,135).In eukaryotes,two morphologically distinct
types of chromatin can be distinguished,namely euchromatin and heterochromatin (28,39)(Fig.2C ).Euchromatin is asso-
ciated with gene-rich and transcriptionally active domains of disperd appearance,characterized biochemically by hyper-acetylation of histones and hypomethylation of both histones and DNA.In contrast,highly condend heterochromatin is linked to gene-poor and transcriptionally inactive dom
ains,such as centromeres and telomeres.Biochemically,heterochro-matin is characterized by hypoacetylation of histones and hypermethylation of histones and DNA (44,82).However,the two morphologically distinct chromatin domains can also have common features.For example,euchromatic promoters asmble a battery of chromatin-modifying activities that in-duce a local closing of chromatin around the promoter suffi-cient to silence transcription.This clod chromatin state around the promoter shares many similarities with the mech-anism of global heterochromatic silencing (42).While histone modifications and DNA methylation have been recognized as canonical epigenetic modifications,non-coding RNAs (ncRNAs)have been recently recognized as players in chromatin remodeling,primarily involved in hetero-chromatin formation and transcriptional or posttranscriptional gene silencing.Three major species of ncRNAs have been identified in mammalian cells:1)small interfering RNAs (siRNAs),molecules of 21–25nucleotides originated from double-stranded RNA that are targeted to chromatin and par-ticipate in gene silencing and in the asmbly of heterochro-matic domains (85);2)micro-RNAs (miRNAs),generated from individual RNA molecules that form hairpin structures,induce posttranscriptional silencing by inhibiting translation (50);3)Piwi-associated RNAs,molecules of 28–33nucleo-tides function in preventing the mobility of transposons (3).The role of ncRNAs in genome function and integrity is only beginning to be unraveled.
DNA METHYLATION
DNA methylation is one of the best understood modifica-tions of chromatin,with crucial roles in gene expression and imprinting,defen against viral quences,inhibition of re-combination,as well as asmbly of heterochromatin (11).Three active DNMT activities (DNMT1,DNMT3a,and DNMT3b)have been identified in humans and mice (93,94)(Fig.3).DNMT1functions primarily as maintenance DNMT,responsible for copying the parental-strand DNA methylation pattern onto the daughter strand after each round of DNA replication.DNMT3a and DNMT3b function as de novo DNMTs,although they can also maintain methylation patterns.DNA methylation is associated with the induction of a clod chromatin state by recruitment of protein complexes that bear repressive chromatin modifying activities,including MBD (methyl-CpG-binding domain)proteins and histone deacety-la (HDAC)-containing complexes (4,65).Cytosine methyl-ation at euchromatic promoters participates in switching off the corresponding genes.At heterochromatic domains,it partici-pates in the asmbly of the highly compacted chromatin characteristic of the domains.Aberrant DNA
methylation
Fig.1.Model of how genetic and epigenetic alterations
contribute to aging and cancer.Genetic and epigenetic
alterations contribute toward the pathogenesis of aging
and aging-related dias,especially cancer.Genetic
alterations,such as chromosomal deletions,DNA rear-
rangements,gene amplifications,and mutations,can
initiate aging and cancer phenotypes.Epigenetic alter-
ations,including changes in DNA methylation,histone
modifications,and levels of expression of noncoding
RNAs,also contribute to the phenotypes.Epigenetic
changes may directly trigger aging and cancer pheno-
types,or prime cells to make them more susceptible to
subquent genetic or epigenetic alterations.Review
编织地垫
587
EPIGENETIC ALTERATIONS IN AGING at South Univ of Sci and Tech of China on April 10, 2013
/Downloaded from
patterns have been linked to genomic instability and incread mutation rates,hallmarks of dia,especially cancer (23,74).Ground-breaking studies performed in rat brain and heart showed a global loss of DNA methylation during aging (127),which was later confirmed in different tissues from rat,mou,and cow (102),in primary fibroblasts from mice,hamsters,and humans grown in culture (134),and in human lymphocytes (29)and peripheral blood cells (14,38).Paradoxically,a variety of specific loci become hypermethylated in normal tissues during aging (35).A study using T-lymphocytes iso-lated from individuals of different ages,ranging from new-borns to elderly people,showed hypermethylation of ϳ1%of the loci examined with increasing age.Comparable changes in DNA methylation at the loci were obrved in other tissues (124).Similarly,a study of changes in DNA methylation in the human cerebral cortex identified a marked increa in cytosine methylation at 8out of 50loci examined (114).Specific examples of genes that are hypermethylated during aging include the estrogen receptor
(ER)(55),insulin-like growth factor-II (IGF-II)(56);p14ARF (110);p16ink4a (116),E-cad-herin (17),c-fos
(24),and collagen-␣1(121).Interestingly,many of the promoters are also hypermethylated during tumorigenesis,suggesting a role in the incread cancer sus-ceptibility associated with
aging.
Fig. 2.The nucleosome,chromatin,and specific marks.
如何做辣椒酱A :diagram of a nucleosome,formed by an octamer of histones
wrapped around by DNA.Histone tails protruding from the
nucleosome core are shown with a variety of posttranslational
modifications.DNA methylation and binding of noncoding
RNAs (ncRNAs)are also shown.B :the four histone tails are
shown with the corresponding posttranslational modifications
at specific residues.C :diagram illustrating the differences
between euchromatin and heterochromatin domains.Euchro-
matin is characterized by hyperacetylation of histones and
hypomethylation of histones and DNA.In contrast,hetero-
chromatin shows hypoacetylation of histones and hypermeth-
ylation of histones and DNA.Review
588EPIGENETIC ALTERATIONS IN AGING
at South Univ of Sci and Tech of China on April 10, 2013
/Downloaded from
The different lines of evidence indicate that a global hypomethylation of the genome accompanies the aging pro-cess,concomitant with incread methylation of specific gene
promoters (19,32)(Fig.3).The molecular mechanisms behind the changes in DNA methylation patterns during aging re-main unknown.Transcriptional control of DNMTs was shown to be altered in aged and transformed human fibroblasts (21).
In fact,it was propod that the global decrea in DNA methylation could stem from a progressive decrea in the efficacy of DNMT1activity on heterochromatic domains dur-ing aging (21,35).In contrast,the hypermethylation of specific promoter CpG islands could be brought about by overexpres-sion of the de novo DNMTs.In particular,upregulation of DNMT3b was reported in cultured fibroblasts (21,35).Future studies need to determine whether transcriptional changes are ind
eed responsible for the accumulation of DNA methylation alterations during aging,and whether the changes increa cancer susceptibility with age.中国铁路的发展
HISTONE ACETYLATION/DEACETYLATION
Histone acetyltransferas (HAT)and HDAC modulate the addition or removal of acetyl groups on histones,as means to regulate transcription (7)(Fig.4).Acetylated lysine residues rve as binding platforms for proteins that contain the bromo-domain protein module,found in some transcription factors,
as
Fig.3.DNA methylation in aging and cancer.The different
proteins playing a role in DNA methylation are shown with
their reported molecular activity and cellular function.A前台的工作内容
summary of the changes obrved in DNA methylation
patterns during cancer and aging by different studies are小李杜指的是谁
also shown.Both changes at a global level and at specific
gene promoters are indicated.ER,estrogen receptor;
BRCA1,breast cancer 1;APC,adenomatosis polyposis
coli.
Fig. 4.Histone-modifying activities in aging
含有鸟的成语and cancer.Listing of the major class of
大学生如何就业histone-modifying activities indicate their spe-
cific activities and reported cellular function.
HDACs,histone deacetylas;HATs,histone
acetyltransferas;HMTs,histone methyltrans-
feras.In the ca of HMTs,the specific lysine
residues that are methylated and their function
are indicated.A summary of the changes ob-
rved in histones modifications during aging
and cancer is also shown.Note that the changes
in SIRT1expression and H4K20me3levels dur-
ing aging and cancer go in the opposite direc-
tion.See text for definition of histone acronyms.Review
589
EPIGENETIC ALTERATIONS IN AGING at South Univ of Sci and Tech of China on April 10, 2013/Downloaded from
