scholarly journals The H19 Differentially Methylated Region Marks the Parental Origin of a Heterologous Locus without Gametic DNA Methylation

2004 ◽  
Vol 24 (9) ◽  
pp. 3588-3595 ◽  
Author(s):  
Kye-Yoon Park ◽  
Elizabeth A. Sellars ◽  
Alexander Grinberg ◽  
Sing-Ping Huang ◽  
Karl Pfeifer
Keyword(s):  
Dna Methylation ◽  
Mouse Chromosome ◽  
Germ Line ◽  
Transcriptional Silencing ◽  
Chromosome 7 ◽  
Differentially Methylated Region ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Chromosome 5 ◽  
The Third

ABSTRACT Igf2 and H19 are coordinately regulated imprinted genes physically linked on the distal end of mouse chromosome 7. Genetic analyses demonstrate that the differentially methylated region (DMR) upstream of the H19 gene is necessary for three distinct functions: transcriptional insulation of the maternal Igf2 allele, transcriptional silencing of paternal H19 allele, and marking of the parental origin of the two chromosomes. To test the sufficiency of the DMR for the third function, we inserted DMR at two heterologous positions in the genome, downstream of H19 and at the alpha-fetoprotein locus on chromosome 5. Our results demonstrate that the DMR alone is sufficient to act as a mark of parental origin. Moreover, this activity is not dependent on germ line differences in DMR methylation. Thus, the DMR can mark its parental origin by a mechanism independent of its own DNA methylation.

The inheritance of germline-specific epigenetic modifications during development

1993 ◽  
Vol 339 (1288) ◽  
pp. 165-172 ◽  
Keyword(s):  
Mouse Chromosome ◽  
Germ Line ◽  
Epigenetic Modification ◽  
Embryonic Stem ◽  
Epigenetic Inheritance ◽  
Epigenetic Modifications ◽  
Chromosome 7 ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Female Germline

Parental genomes in mammals are programmed in the germline with heritable epigenetic modifications that exert control on the expression of specific (imprinted) genes. DNA methylation is one form of epigenetic modification which shows marked genome-wide variations in the germline and during early development. Certain transgene loci also demonstrate (reversible) germline-specific methylation imprints that are heritable in somatic tissues during development. Recently, four endogenous genes have been identified whose expression is dependent on their parental origin. The mechanism of genomic imprinting and the role of imprinted genes during development is beginning to be analysed. Three of these genes map to the mouse chromosome 7. Human chromosomes 11p13, 11p15, and 15ql 1-13 are associated with disorders exhibiting parental origin effects in their patterns of inheritance. These regions share syntenic homology with mouse chromosome 7. The relationship between parental imprints, germ line-dependent epigenetic inheritance and totipotency is also under investigation using embryonic stem cells derived from the epiblast. These cells are pluripotent or totipotent and evidence indicates the presence of at least the primary parental imprints. However, imprints inherited from the paternal germline in androgenetic cells are apparently more stable than those from the female germline in parthenogenetic cells.

scholarly journals Epigenetic and Phenotypic Consequences of a Truncation Disrupting the Imprinted Domain on Distal Mouse Chromosome 7

2007 ◽  
Vol 28 (3) ◽  
pp. 1092-1103 ◽  
Author(s):  
Rosemary Oh ◽  
Rita Ho ◽  
Lynn Mar ◽  
Marina Gertsenstein ◽  
Jana Paderova ◽  
...  
Keyword(s):  
Mouse Chromosome ◽  
Germ Line ◽  
Embryonic Stem ◽  
Functional Independence ◽  
Chromosome 7 ◽  
Paternal Allele ◽  
Imprinted Genes ◽  
Evolutionarily Conserved ◽  
Germ Line Transmission ◽  
Dependent Mechanism

ABSTRACT The distal end of mouse chromosome 7 (Chr 7) contains a large cluster of imprinted genes. In this region two cis-acting imprinting centers, IC1 (H19 DMR) and IC2 (KvDMR1), define proximal and distal subdomains, respectively. To assess the functional independence of IC1 in the context of Chr 7, we developed a recombinase-mediated chromosome truncation strategy in embryonic stem cells and generated a terminal deletion allele, DelTel7, with a breakpoint in between the two subdomains. We obtained germ line transmission of the truncated Chr 7 and viable paternal heterozygotes, confirming the absence of developmentally required paternally expressed genes distal of Ins2. Conversely, maternal transmission of DelTel7 causes a midgestational lethality, consistent with loss of maternally expressed genes in the IC2 subdomain. Expression and DNA methylation analyses on DelTel7 heterozygotes demonstrate the independent imprinting of IC1 in absence of the entire IC2 subdomain. The evolutionarily conserved linkage between the subdomains is therefore not required for IC1 imprinting on Chr 7. Importantly, the developmental phenotype of maternal heterozygotes is rescued fully by a paternally inherited deletion of IC2. Thus, all the imprinted genes located in the region and required for normal development are silenced by an IC2-dependent mechanism on the paternal allele.

Parental Imprinting on Mouse Chromosome 7

1996 ◽  
Vol 45 (1-2) ◽  
pp. 41-41
Author(s):  
A.C. Ferguson-Smith
Keyword(s):  
Mouse Chromosome ◽  
Uniparental Disomy ◽  
Chromosome 7 ◽  
Paternal Allele ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Clear Cut ◽  
Parental Imprinting ◽  
H19 Gene ◽  
Mutant Phenotypes

Genetic studies have shown that both a maternally and paternally inherited copy of mouse chromosome 7 are essential for normal embryogenesis. When the parental dosage is altered, such as in maternal or paternal uniparental disomy for chromosome 7 (UPD7), the resulting embryos die. This is due to the altered dosage of imprinted genes which are normally expressed only from the paternally or maternally inherited chromosome homologue. Several genes on mouse chromosome 7 are subject to parental imprinting. Mutant phenotypes seen in UPD7 embryos and chimaeras can be explained by the altered dosage of some of these genes.The mechanism(s) that causes genes to be expressed in a parental origin specific manner has not yet been determined but is believed to involve germline specific modifications to DNA and/or chromatin which are acted upon after fertilisation to affect the activity of imprinted genes. Two genes, H19 and Igf2, are located 90kb apart on the distal end of chromosome 7 and are imprinted reciprocally with the maternally inherited allele of HI9 and paternally inherited allele of Igf2 being expressed. We have used UPD7 embryos to identify epigenetic modifications that distinguish the two parental alleles in the H19 and Igf2 domain by comparing DNA and chromatin from normal and maternal UPD cobceptuses. Clear cut differences in DNA methylation and chromatin compaction were observed for the H19 gene with the paternal allele exhibiting promoter methylation and nuclease insensitivity. These were not found in sperm. In addition, no major differences were noted for the Igf2 gene, although subtle parental origin specific modifications were found. These studies suggest that the two genes may share a common regulatory mechanism which controls their reciprocal imprinting.

scholarly journals The Epimorphin Gene Is Highly Conserved among Humans, Mice, and Rats and Maps to Human Chromosome 7, Mouse Chromosome 5, and Rat Chromosome 12

Genomics ◽  
1996 ◽  
Vol 37 (3) ◽  
pp. 386-389 ◽  
Author(s):  
Hongbin Zha ◽  
Elaine F. Remmers ◽  
Claude Szpirer ◽  
Josiane Szpirer ◽  
Heying Zhang ◽  
...  
Keyword(s):  
Human Chromosome ◽  
Mouse Chromosome ◽  
Chromosome 7 ◽  
Chromosome 12 ◽  
Chromosome 5 ◽  
Human Chromosome 7

Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells

Development ◽  
2002 ◽  
Vol 129 (8) ◽  
pp. 1807-1817 ◽  
Author(s):  
Jiyoung Lee ◽  
Kimiko Inoue ◽  
Ryuichi Ono ◽  
Narumi Ogonuki ◽  
Takashi Kohda ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genomic Imprinting ◽  
Nuclear Transfer ◽  
Monoallelic Expression ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Specific Expression ◽  
Male And Female ◽  
Imprinted Gene ◽  
Methylation Patterns

Genomic imprinting is an epigenetic mechanism that causes functional differences between paternal and maternal genomes, and plays an essential role in mammalian development. Stage-specific changes in the DNA methylation patterns of imprinted genes suggest that their imprints are erased some time during the primordial germ cell (PGC) stage, before their gametic patterns are re-established during gametogenesis according to the sex of individuals. To define the exact timing and pattern of the erasure process, we have analyzed parental-origin-specific expression of imprinted genes and DNA methylation patterns of differentially methylated regions (DMRs) in embryos, each derived from a single day 11.5 to day 13.5 PGC by nuclear transfer. Cloned embryos produced from day 12.5 to day 13.5 PGCs showed growth retardation and early embryonic lethality around day 9.5. Imprinted genes lost their parental-origin-specific expression patterns completely and became biallelic or silenced. We confirmed that clones derived from both male and female PGCs gave the same result, demonstrating the existence of a common default state of genomic imprinting to male and female germlines. When we produced clone embryos from day 11.5 PGCs, their development was significantly improved, allowing them to survive until at least the day 11.5 embryonic stage. Interestingly, several intermediate states of genomic imprinting between somatic cell states and the default states were seen in these embryos. Loss of the monoallelic expression of imprinted genes proceeded in a step-wise manner coordinated specifically for each imprinted gene. DNA demethylation of the DMRs of the imprinted genes in exact accordance with the loss of their imprinted monoallelic expression was also observed. Analysis of DNA methylation in day 10.5 to day 12.5 PGCs demonstrated that PGC clones represented the DNA methylation status of donor PGCs well. These findings provide strong evidence that the erasure process of genomic imprinting memory proceeds in the day 10.5 to day 11.5 PGCs, with the timing precisely controlled for each imprinted gene. The nuclear transfer technique enabled us to analyze the imprinting status of each PGC and clearly demonstrated a close relationship between expression and DNA methylation patterns and the ability of imprinted genes to support development.

Multilocus methylation defects in imprinting disorders

2015 ◽  
Vol 6 (1) ◽  
pp. 47-57 ◽  
Author(s):  
Deborah J.G. Mackay ◽  
Thomas Eggermann ◽  
Karin Buiting ◽  
Intza Garin ◽  
Irène Netchine ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Normal Development ◽  
Genetic Diseases ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Mammalian Development ◽  
Imprinting Disorders ◽  
Common Process ◽  
Genetic Mechanisms ◽  
Methylation Defects

AbstractMammals inherit two complete sets of chromosomes, one from the father and one from the mother, and most autosomal genes are expressed from both maternal and paternal alleles. In imprinted genes, the expression of the allele is dependent upon its parental origin. Appropriate regulation of imprinted genes is important for normal development, with several genetic diseases associated with imprinting defects. A common process for controlling gene activity is methylation. The first steps for understanding the functions of DNA methylation and its regulation in mammalian development have led us to identify common (epi)genetic mechanisms involved in the eight human congenital imprinting disorders.

scholarly journals Mechanism of imprinting on mouse distal chromosome 7

1998 ◽  
Vol 72 (3) ◽  
pp. 237-245 ◽  
Author(s):  
JUSTIN F-X. AINSCOUGH ◽  
ROSALIND M. JOHN ◽  
M. AZIM SURANI
Keyword(s):  
Chromosome 7 ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Critical Feature ◽  
Male Germline ◽  
Domain Type ◽  
Distal Chromosome ◽  
Type Mode ◽  
Single Allele ◽  
Female Germline

Genomic imprinting is an epigenetic mode of gene regulation that results in expression of the autosomal ‘imprinted’ genes from only a single allele, determined exclusively by parental origin. To date over 20 imprinted genes have been identified in mouse and man and these appear to lie in clusters in restricted regions on a subset of chromosomes. This may be a critical feature of imprinting suggesting a domain-type mode of regulation. Imprinted domains are replicated asynchronously, show sex-specific meiotic recombination frequencies and have CpG-rich regions that are differentially methylated, often associated with the imprinted genes themselves. Mouse distal chromosome 7 is one such domain, containing at least nine imprinted genes spanning over 1 Mb of DNA. For the maternally expressed p57Kip2 gene, passage through the female germline is essential to generate the active state, whereas passage through the male germline is needed to force the maternally expressed H19 gene into an inactive state. It is therefore possible that the mouse distal chromosome 7 imprinted domain is actually composed of two or more independently regulated subdomains.

scholarly journals Dietary supplementation with polyunsaturated fatty acid during pregnancy modulates DNA methylation at IGF2/H19 imprinted genes and growth of infants

2014 ◽  
Vol 46 (23) ◽  
pp. 851-857 ◽  
Author(s):  
Ho-Sun Lee ◽  
Albino Barraza-Villarreal ◽  
Carine Biessy ◽  
Talita Duarte-Salles ◽  
Peter D. Sly ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mononuclear Cells ◽  
Dietary Supplementation ◽  
Positive Association ◽  
Child Growth ◽  
Normal Weight ◽  
Differentially Methylated Region ◽  
Control Group ◽  
Imprinted Genes ◽  
Maternal Body Mass Index

Epigenetic regulation of imprinted genes is regarded as a highly plausible explanation for linking dietary exposures in early life with the onset of diseases during childhood and adulthood. We sought to test whether prenatal dietary supplementation with docosahexaenoic acid (DHA) during pregnancy may modulate epigenetic states at birth. This study was based on a randomized intervention trial conducted in Mexican pregnant women supplemented daily with 400 mg of DHA or a placebo from gestation week 18–22 to parturition. We applied quantitative profiling of DNA methylation states at IGF2 promoter 3 ( IGF2 P3), IGF2 differentially methylated region (DMR), and H19 DMR in cord blood mononuclear cells of the DHA-supplemented group ( n = 131) and the control group ( n = 130). In stratified analyses, DNA methylation levels in IGF2 P3 were significantly higher in the DHA group than the control group in preterm infants ( P = 0.04). We also observed a positive association between DNA methylation levels and maternal body mass index; IGF2 DMR methylation was higher in the DHA group than the control group in infants of overweight mothers ( P = 0.03). In addition, at H19 DMR, methylation levels were significantly lower in the DHA group than the control group in infants of normal weight mothers ( P = 0.01). Finally, methylation levels at IGF2/H19 imprinted regions were associated with maternal BMI. These findings suggest that epigenetic mechanisms may be modulated by DHA, with potential impacts on child growth and development.

scholarly journals Multiple Segmental Uniparental Disomy Associated with Abnormal DNA Methylation of Imprinted Loci in Silver-Russell Syndrome

2012 ◽  
Vol 97 (11) ◽  
pp. E2188-E2193 ◽  
Author(s):  
Renuka P. Dias ◽  
Irina Bogdarina ◽  
Jean-Baptiste Cazier ◽  
Charles Buchanan ◽  
Malcolm C. Donaldson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mrna Expression ◽  
Single Nucleotide Polymorphism Array ◽  
Uniparental Disomy ◽  
Postnatal Growth ◽  
Chromosome 7 ◽  
Imprinted Genes ◽  
Methylation Array ◽  
Maternal Uniparental Disomy ◽  
Silver Russell Syndrome

Background: Silver-Russell syndrome (SRS; online inheritance in man 180860) is a low-birth-weight syndrome characterized by postnatal growth restriction and variable dysmorphic features. Although maternal uniparental disomy (UPD) of chromosome 7 and hypomethylation of H19 have been reported in up to 50% of all cases, no unifying mechanism is apparent. Subjects and Methods: Ten patients and their parents were studied using the Illumina GoldenGate methylation array and the Illumina 370K HumHap single-nucleotide polymorphism array to identify aberrations in DNA methylation as well as genomic changes including copy number changes and uniparental disomy events. Results: We found evidence of UPD events outside chromosome 7 in all patients. In up to 30% of patients with SRS, DNA methylation changes occur in imprinted gene loci outside 11p15.5 (PEG3, PLAGL1, and GRB10), not previously consistently linked with SRS. Furthermore, hypermethylation of GRB10 was associated with increased mRNA expression. In addition, 20% of patients appear to have DNA methylation abnormalities within multiple loci. Not all the imprinted loci with methylation defects were affected directly by UPD. Conclusions: The association of widespread UPD associated with abnormal methylation and mRNA expression in imprinted genes in SRS is consistent with the concept of UPD as an initial genomic abnormality leading to unstable DNA methylation within the regulatory network of imprinted genes. Furthermore, disruption of any one of these genes may contribute to the heterogeneous clinical spectrum of SRS.

scholarly journals Gamete imprinting: setting epigenetic patterns for the next generation

2006 ◽  
Vol 18 (2) ◽  
pp. 63 ◽  
Author(s):  
Jacquetta M. Trasler
Keyword(s):  
Dna Methylation ◽  
Genomic Dna ◽  
Germ Line ◽  
Imprinted Genes ◽  
Specific Expression ◽  
Placental Function ◽  
Early Embryos ◽  
Parent Of Origin ◽  
Methylation Patterns ◽  
Epigenetic Patterns

The acquisition of genomic DNA methylation patterns, including those important for development, begins in the germ line. In particular, imprinted genes are differentially marked in the developing male and female germ cells to ensure parent-of-origin-specific expression in the offspring. Abnormalities in imprints are associated with perturbations in growth, placental function, neurobehavioural processes and carcinogenesis. Based, for the most part, on data from the well-characterised mouse model, the present review will describe recent studies on the timing and mechanisms underlying the acquisition and maintenance of DNA methylation patterns in gametes and early embryos, as well as the consequences of altering these patterns.

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