1、SnapShot:Imprinted Gene ClustersJoanne L.Thorvaldsen and Marisa S.BartolomeiDepartment of Cell and Developmental Biology,University of Pennsylvania School of Medicine,Philadelphia,PA 19104,USAImprinted gene loci1Associated Imprinted ncRnAsother Associated Imprinted genes2germline dmRs3Imprinting mec
2、hanism4mouse locus/Human locus5Association with Human disease or syndrome6Igf2H19Ins27H19 DMD(ICR)CTCF-dependent insulator7qF5/11p15.5 Beckwith-Wiedemann syndrome,Silver-Russell syndrome Igf2r8 Air8,*Slc22a27,9,Slc22a37,9Air promoter(ICR)long ncRNA transcription17qA1/6q25.3SnrpnUbe3a-ATS*,snoRNAs10A
3、tp10a,Ube3a7,Snurf,Ndn,Magel2,Mkrn3,Peg12Snrpn promoter and exon1:PWS-IC(ICR)11long ncRNA transcription?7qB5/15q11.2Prader-Willi syndrome,Angelman syndrome12Cdkn1cKcnq1ot1*Osbp157,Nap1l47,9,Phlda27,9,Slc22a18,Msuit19,Kcnq17,Cd817,9,Ascl27,9,Tssc47,9 Kcnq1ot1 promoter:KvDMR1(ICR)long ncRNA transcript
4、ion7qF5/11q15.4Beckwith-Wiedemann syndromeDlk1Gtl2,anti-Rtl1 microRNAs8,Rian snoRNAs8,Mirg microRNAs8,10Rtl18,Dio3Intergenic DMR:IG-DMR(ICR)ND12qF1/14q32.2Gnas7Nespas,Gnas exon 1AGnasxl,NespGnasxl and Nespas promoter DMR(primary ICR),Gnas exon 1a promoter DMR(secondary ICR)ND2qH4/20q13.32 Albright h
5、ereditary osteodystrophy,Pseudohypoparathyroidism 1a+1b,McCune-Albright syndromePeg3Zim2,Zim114,Usp29,Zim3,Zfp264Peg 3 promoter and exon1 ND7qA1/19q13.43 Plagl1(Zac1)7Hymai7,9Hymai exon1ND10qA2/6q24.2Transient neonatal diabetes mellitusPeg10Sgce,Ppp1r9a7,Asb49Peg10 and Sgce promoterND6qA1/7q21.3 Myo
6、clonus-dystonia syndrome13Mest(Peg1)Copg2as8Copg29,Klf14Mest-promoter-exon1ND6qA3.3/7q32.2 Rasgrf17,94930524O08Rik7,930 kb Rasgrf1 DMR-Repeat(ICR)CTCF-dependent insulator?9qE3.1/15q25.1 Grb107Grb10 brain isoform7Grb10 CpG Island 2ND11qA1/7p12.2 Zrsr1(U2af1-rs1)14Commd17Zrsr1 CpG IslandND11qA3.2/5q22
7、.2 Xlr3b14Xlr4b14,Xlr4c14NDXqA7.3 Xist7,9Tsix7,9long ncRNA transcriptionXqD/Xq13.2 X Paternally expressed genesX Maternally expressed genesX Differentially methylated regions(DMRs)methylated on the paternal alleleX DMRs methylated on the maternal allele*Transcription of ncRNAs essential for imprinti
8、ng control of the locus.The majority of imprinted genes are found in conserved clusters in the mammalian genome.Shown are mouse imprinted genes that are part of larger imprinting clusters(variations in human are noted).Each cluster has a prominent gene indicated in the left most column and one or mo
9、re noncoding(nc)RNAs,which in many cases are critical for the domain-wide regulation of the cluster.Also shown are other associated imprinted genes that typically are jointly regulated through a common imprinting control region(ICR).Single imprinted gene loci are not included in this table and can b
10、e found using the following web resources:MRC,Harwell,Mammalian Genet-ics Unit,Genomic Imprinting:http:/www.mgu.har.mrc.ac.uk/research/imprinting;University of Otago,Catalogue of Parent of Origin Effects:http:/igc.otago.ac.nz/home.html.The offi cial gene names are shown,with some more familiar names
11、 indicated in parentheses.1The prominent protein-coding gene within each cluster is listed in this column.The exception to this is Xist,which encodes a long ncRNA that coats the inactive X chromosome in females and is responsible for X inactivation.2In most cases these associated genes are jointly r
12、egulated through the linked ICR.3ICR indicates that the DMR has been validated as an imprinting control region by gene targeting studies in mice:deletion or mutation of the DMR results in loss of imprinting of at least one gene.4The mechanism of imprinting is unknown for most of the clusters(designa
13、ted as not determined,ND)but currently two types of clusters have been identifi ed.In one type of cluster a CTCF-dependent methylation-sensitive insulator controls imprinted gene expression.In the second type of cluster imprinting requires transcription of a long ncRNA that is usually initiated from
14、 a hypomethylated DMR/promoter.A question mark indicates that the mechanism is still largely speculative.5UCSC Mouse build February 2006 and Human build March 2006.6Deletion,mutation,or aberrant expression of the genes in the cluster results in the listed human disease.Additionally,ICR deletions and
15、 methylation abnormalities can cause these syndromes.For most human imprinted loci,maternal and/or uniparental disomies are associated with distinct abnormal phenotypes.Only proven associations are shown.7Tissue-specifi c imprinting.8Not imprinted in human.9Imprinting status in human is unknown or c
16、onfl icting.10All short ncRNAs at this locus may be part of a longer ncRNA.11The ICR regulating the paternally expressed genes has been identifi ed for mouse and human(PWS-IC)whereas the ICR that regulates the maternally expressed genes has been identifi ed in humans but not in mice(AS-IC).However,U
17、be3a-ATS transcription appears to be important for regulating both paternal and maternal genes at this locus.12Loss of multiple paternally expressed genes is responsible for Prader-Willi syndrome(PWS)and loss of Ube3a expression is responsible for Angelman syndrome(AS).13Mutations in SGCE are found
18、in patients with Myoclonus dystonia syndrome.14No human ortholog present at locus.See online version for references and acknowledgements.958 Cell 130,September 7,2007 2007 Elsevier Inc.DOI 10.1016/j.cell.2007.08.033SnapShot:Imprinted Gene ClustersJoanne L.Thorvaldsen and Marisa S.BartolomeiDepartmen
19、t of Cell and Developmental Biology,University of Pennsylvania School of Medicine,Philadelphia,PA 19104,USARefeRencesEdwards,C.A.,and Ferguson-Smith,A.C.(2007).Mechanisms regulating imprinted genes in clusters.Curr.Opin.Cell Biol.19,281289.Lalande,M.,and Calciano,M.A.(2007).Molecular epigenetics of
20、Angelman syndrome.Cell.Mol.Life Sci.64,947960.ONeill,M.J.(2005).The influence of non-coding RNAs on allele-specific gene expression in mammals.Hum.Mol.Genet.14 Spec No 1,R113-R120.Pauler,F.M.,Koerner,M.V.,and Barlow,D.P.(2007).Silencing by imprinted noncoding RNAs:Is transcription the answer?Trends
21、Genet.23,284292.Peery,E.G.,Elmore,M.D.,Resnick,J.L.,Brannan,C.I.,and Johnstone,K.A.(2007).A targeted deletion upstream of Snrpn does not result in an imprinting defect.Mamm.Genome 18,255262.Plagge,A.,and Kelsey,G.(2006).Imprinting the Gnas locus.Cytogenet.Genome Res.113,178187.Smith,F.M.,Garfield,A.
22、S.,and Ward,A.(2006).Regulation of growth and metabolism by imprinted genes.Cytogenet.Genome Res.113,279291.Smith,A.C.,Choufani,S.,Ferreira,J.C.,and Weksberg,R.(2007).Growth regulation,imprinted genes,and chromosome 11p15.5.Pediatr.Res.61,43R47R.Valleley,E.M.,Cordery,S.F.,and Bonthron,D.T.(2007).Tis
23、sue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of mono-allelic and biallelic promoters.Hum.Mol.Genet.16,972981.Varrault,A.,Gueydan,C.,Delalbre,A.,Bellmann,A.,Houssami,S.,Aknin,C.,Severac,D.,Chotard,L.,Kahli,M.,Le Digarcher,A.,et al.(2006).Zac1 regu
24、lates an imprinted gene network critically involved in the control of embryonic growth.Dev.Cell 11,711722.Verona,R.I.,Mann,M.R.,and Bartolomei,M.S.(2003).Genomic imprinting:Intricacies of epigenetic regulation in clusters.Annu.Rev.Cell Dev.Biol.19,237259.Wood,A.J.,and Oakey,R.J.(2006).Genomic imprin
25、ting in mammals:Emerging themes and established theories.PLoS Genet.2,e147.Zhang,Z.,Joh,K.,Yatsuki,H.,Wang,Y.,Arai,Y.,Soejima,H.,Higashimoto,K.,Iwasaka,T.,and Mukai,T.(2006).Comparative analyses of genomic imprinting and CpG island-methylation in mouse Murr1 and human MURR1 loci revealed a putative imprinting control region in mice.Gene 366,7786.AcknowledgementsWe thank Gavin Kelsey,Anne Ferguson-Smith,and Jeannie Lee for their helpful discussions and the NIH for funding(GM51279 and GM74768).958.e1 Cell 130,September 7,2007 2007 Elsevier Inc.DOI 10.1016/j.cell.2007.08.033