ISSN:0192-253X    

DOI:10.1002/dvg.1020170302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThis review covers data on changing patterns of DNA methylation and the regulation of gene expression in mouse embryonic development. Global demethylation occurs from the eight‐cell stage to the blastocyst stage in pre‐implantation embryos, and global de novo methylation begins at implantation. We have used X‐chromosome inactivation in female embryos as a model system to study specific CpG sites in the X‐linkedPgk‐1andGópdhousekeeping genes and in the imprinted regulatoryXistgene to elucidate the role of methylation in the initiation and maintenance of differential gene activity. Methyl‐ation of the X‐linked housekeeping genes occurs very close in time to their inactivation, thus raising the question as to whether methylation could be causal to inactivation, as well as being involved in its maintenance. A methylation difference between sperm and eggs in the promoter region of theXistgene, located at the X‐chromosome inactivation centre, is correlated with imprinted preferential inactivation of the paternal X chromosome in extra‐embryonic tissues. Based on our data, a picture of the inheritance of methylation imprints and speculation on the significance of theXistimprint in development is presented. On a more general level, an hypothesis of evolution by “adaptive epige‐netic/genetic inheritance” is considered. This proposes modification of germ line DNA in response to a change in environment and mutation at the site of modification (e.g., of methylated cytosine to thymine). Epigenetic inheritance could function to shift patterns of gene expression to buffer the evolving system against changes in environment. If the altered patterns of gene activity and inactivity persist, the modifications may become “fixed” as mutations; alternatively, previously silenced gene networks might be recruited into function, thus appearing as if they are “acquired characteristics.” An extension of this hypothesis is “foreign gene acquisition and sorting” (selection or silencing of gene function according to use). “Kidnapping” and sorting of foreign genes in this way could explain the observation that increased complexity in evolution is associated with more “junk” DNA. Adaptive epigenetic/genetic inheritance challenges the “central dogma” that information is unidirectional from the DNA to protein and the idea that Darwinian random mutation and selection are the sole

ISSN:0192-253X    

DOI:10.1002/dvg.1020170303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractWe have begun a search for heritable variation in X‐chromosome inactivation pattern in normal females to determine whether there is a genetic effect on the imprinting of X‐chromosome inactivation in humans. We have performed a quantitative analysis of X‐chromosome inactivation in lymphocytes from mothers in normal, three‐generation families. Eight mothers and 12 grandmothers exhibited evidence of highly skewed patterns of X‐chromosome inactivation. We observed that the male offspring of females with skewed X‐inactivation patterns were three times more likely to inherit alleles at loci that were located on the inactive X chromosome (Xi) than the active X chromosome (Xa). The region of the X chromosome for which this phenomenon was observed extends from XP11 to ‐Xq22. We have also examined X‐chromosome inactivation patterns in 21 unaffected mothers of male bilateral sporadic retinoblastoma patients. Six of these mothers had skewed patterns of X‐chromosome inactivation. In contrast to the tendency for male offspring of skewed mothers from nondisease families to inherit alleles from the inactive X chromosome, five of the six affected males inherited the androgen receptor alleles from the active X chromosome of their mother. © 19

ISSN:0192-253X    

DOI:10.1002/dvg.1020170304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe existence of parentally imprinted gene expression in the somatic tissues of mammals and plants can be explained by a theory of intragenomic genetic conflict, which is a logical extension of classical parent‐offspring conflict theory. This theory unites conceptually the phenomena of autosomal imprinting and X‐chromosome inactivation. We argue that recent experimental studies of X‐chromosome inactivation and andro‐genetic development address previously published predictions of the conflict theory, and we discuss possible explanations for the occurrence of random X‐inactivation in the somatic tissues of eutherians. © 1995 Wiley

ISSN:0192-253X    

DOI:10.1002/dvg.1020170305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractA quantitative RT‐PCR approach has been used to examine the expression of a number of X‐linked genes during preimplan‐tation development of normal mouse embryos and in androgenetic and gynogenetic mouse embryos. The data reveal moderately reduced expression of thePrps1, Hprt, andPdha1mRNAs in androge‐netic eight‐cell and morula stage embryos, but not in androgenetic blastocysts.Pgk1mRNA abundance was severely reduced in androgenones at the eight‐cell and morula stages and remained reduced, but to a lesser degree, in androgenetic blastocysts. These data indicate that paternally inherited X chromosomes are at least partially repressed in androgenones, as they are in normal XX embryos, and that the degree of this repression is chromosome position‐dependent or gene‐dependent. Gynogenetic embryos expressed elevated amounts of some mRNAs at the morula and blas‐tocyst stages, indicative of a delay in dosage compensation that may be chromosome position‐dependent. TheXistRNA was expressed at a greater abundance in androgenones than in gynogenones at the eight‐cell and morula stages, consistent with previous studies.Xistexpression was observed in both and rogenones and gynogenones at the blas‐tocyst stage. We conclude that the developmental arrest in early androgenones may be, in part, due to reduced expression of essential X‐linked genes, particularly those near the X inactivation center, where as the developmental defects of gyno‐genones and parthenogenones, by contrast, may be partially due to overexpression of X‐linked genes in extraembryonic tissues, possibly those far‐thest away from the X inactivation

ISSN:0192-253X    

DOI:10.1002/dvg.1020170306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractUniparental embryos have been instrumental in studying imprinting because contributions from the parental genomes can be determined unambiguously. In this study, we set out to identify imprinted genes showing differential expression between parthenogenetic and fertilized embryos during preimplantation and early postimplantation stages of development. We identified three genes‐apolipoprotein E, pyruvate kinase‐3, and protein phosphatase 1 gamma‐that represent excellent candidates for imprinted genes, based on the results of the differential screen, their function in differentiation and the cell cycle, and their location within imprinted chromosomal regions. In addition, two novel genes expressed in trophoblast were identified, 1661 and RA81. These genes, together with four known imprinted genes,H19, Igf2r, Igf2, andSnrpn, showed evidence of expression from both parental alleles in early stage embryos, indicating a role for postfertilization processes in regulating imprinted gene function. © 1995 Wiley‐L

ISSN:0192-253X    

DOI:10.1002/dvg.1020170307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractWe have examined the inheritance of a transgene locus in the zebrafish,Daniorerioand demonstrated that its methylation is af fected by the sex of the parent contributing the allele. This parent‐of‐origin effect on the zebrafish transgene appears to be identical to imprinting as seen in mammals except that in zebrafish, passage of the locus through a female tended to decreased its methylation, whereas passage through a male increased it. Methylation of the transgene in gametic tissues differed from somatic tissue with the locus being hypomethylated in sperm and hypermethylated in the unfertilized egg. The potential identification of imprinting in the zebrafish has important ramifications with respect to the evolution of the process as well as for understanding the role of imprinting in mammals. © 1995 Wiley‐Lis

ISSN:0192-253X    

DOI:10.1002/dvg.1020170308

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe insulin‐like growth factor 2(Igf2)gene on distal mouse chromosome 7 is expressed predominantly from the paternal allele. In previous studies we identified two regions of paternal allele‐specific methylation; one at ˜ 3 kb upstream of promoter 1, and a second in the 3′, coding portion of the gene. The 3′ region is methylated in an expressing tissue (fetal liver), whereas in a non‐expressing tissue (fetal brain), it is not methylated. By contrast, in the 5′ region, the paternal allele is highly methylated in all tissues. Here, we have studied another characteristic of chromatin, namely, sensitivity to DNase‐1 and have focused our developmental analysis on the two differentially methylated regions ofIgf2. In the upstream region, four clustered DNase‐I hypersensitive sites (HSS) were detected in embryonic stem (ES) cells and in midgestation embryos, but not in neonatal liver or brain. In promoter 1 (P1), at β 0.3 kb upstream of exon 1, we detected a tissue‐specific HSS that was present in neonatal liver, in which P1 is active, but was absent in ES cells, the embryo, and in neonatal brain. No DNase‐I HSS were detected in the 3′ differentially methylated region ofIgf2. In all these regions, we did not detect differences in DNase‐I sensitivity between the parental chromosomes. These results establish major developmental and tissue‐specific control of chromatin in theIgf2locus. The presence of the HSS upstream ofIgf2precedes transcriptional activation of theIgf2gene and may be indicative of a promoter for another transcript that is transcribed in the opposite direction. The HSS in P1 is largely liver‐specific; this promoter therefore is differently regulated than the more general fetal promoters P2 and P3. Whereas methylation can be allele‐specific, presumably reflecting the gene imprint, the nuclease sensitivity, as detected by our assay, is not. These results, taken together with previous observations, reveal developmental and tissue‐specific complexity in the expression of the parental imprint at the level of chromatin and transcription. We propose that epigenetic features of tissue‐specific control and of the control of allelic expression are intrica

ISSN:0192-253X    

DOI:10.1002/dvg.1020170309

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractParental genomic imprinting is the phenomenon in which the behavior of a gene is modified, depending on the sex of the transmitting parent [Peterson and Sapienza (1993): Annu Rev Genet 27:7–31]. Recent observations have revealed that the inheritance patterns, age‐of‐onset, severity, and etiology of certain human diseases can be explained by aberrations in the establishment or the maintenance of the imprint. Examples include the Prader‐Willi, Angelman, and Beckwith‐Wiedemann syndromes [Nicholls (1994): Am J Hum Genet 54:733–740], malignancy [Sapienza (1990): Biochim Biophys Acta 1072:51–61; Feinberg (1993): Nat Genet 4:110–113], and insulin‐ependent diabetes mellitus (IDDM) [Julieret al. (1994) Nature 354:155–159; Bennettet al. (1995) Nat Genet 9:284–292]. We review the evidence that implicates an imprinted gene in theINS‐IGF2region of chromosome llp15 in the etiology of IDDM (referred to as the IDDM2 locus) and show that in human fetal pancreas,INSis not imprinted, thus providing an argument againstINSas the candidate gene. We also examine imprinting effects on the expression ofIGF2in components of the human immune system believed to be important in IDDM and show imprinted expression in fetal thymus as early as 15 weeks gestation. We demonstrate further that in the circulating mononuclear cells of two individuals, lectin‐stimulatedIGF2transcription was biallelic, indicating relaxation of imprinting, whereas in one individual, transcription was monoallelic. Finally, we review the current available data supporting a role for insulin‐like growth factor‐ll (IGF‐II) in the immune system and, more specifically, discuss the evidence supporting a role for the IGFs in the prevention of apoptosis. These data have led us to formulate a novel hypothesis that could mechanistically explain the involvement of the IDDM2 locus in the pathogenesis

ISSN:0192-253X    

DOI:10.1002/dvg.1020170310

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractIn a search for genes expressed in preimplantation mouse embryos that are important for the earliest steps in differentiation, we identified an abundant mRNA that codes for a sulfated glycoprotein, SGP‐1. The amount of this RNA rises ˜ 100‐fold during preimplantation development to a level approximately equal to that of β‐actin mRNA in blastocysts, although the level of these transcripts per cell remains fairly constant during these stages at ˜ 2,000–4,000 copies. An antisense RNA that is complementary to approximately the last one‐third of the message and contains an open reading frame of 455 nt was found in blastocysts at a 2–3‐fold higher level than the mRNA. In situ hybridization with sense and antisense riboprobes showed that both strands are distributed throughout the embryo. The abundance of the SGP‐1 mRNA indicates that the encoded protein may play an important role in the development of embryos, and the excess of antisense RNA raises the possibility of an unusual mechanism of regulating its expression. © 1

ISSN:0192-253X    

DOI:10.1002/dvg.1020170311

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY