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 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.

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.

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.

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 Genomic imprinting and its role in ethiology of human hereditary diseases

2004 ◽  
Vol 3 (3) ◽  
pp. 8-17
Author(s):  
S. A. Nazarenko
Keyword(s):  
Gene Expression ◽  
Genomic Imprinting ◽  
Special Class ◽  
Growth And Development ◽  
Epigenetic Inheritance ◽  
Hereditary Diseases ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Methylation Of Dna ◽  
Differential Gene

Genomic imprinting is a form of non-Mendelian epigenetic inheritance that is defined by differential gene expression depending on its parental origin — maternal or paternal. It is known about 60 imprinted genes many of which effect significantly on the fetus growth and development. Methylation of DNA cytosine bases that defines the interaction of DNA and proteins identifying the modified bases and controls the gene expression through chromatin compacting-decompacting mechanism, is a main epigenetic genom modifier. Disturbances in monoallelic gene expression lead to the development of a special class of human hereditary diseases — genomic imprinting diseases.

scholarly journals Multiple Imprinted Genes Associated with Prader-Willi Syndrome and Location of an Imprinting Control Element

1996 ◽  
Vol 45 (1-2) ◽  
pp. 87-89
Author(s):  
R.D. Nicholls ◽  
M.T.C. Jong ◽  
C.C. Glenn ◽  
J. Gabriel ◽  
P.K. Rogan ◽  
...  
Keyword(s):  
Genomic Imprinting ◽  
Epigenetic Modification ◽  
Uniparental Disomy ◽  
Paternal Allele ◽  
Control Element ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Mammalian Development ◽  
Specific Expression ◽  
Large Deletions

Our studies aim to identify the mechanisms and genes involved in genomic imprinting in mammalian development and human disease. Imprinting refers to an epigenetic modification of DNA that results in parent-of-origin specific expression during embryogenesis and in the adult. This imprint is reset at each generation, depending on the sex of the parental gametogenesis. Prader-Willi (PWS) and Angelman (AS) syndromes are excellent models for the study of genomic imprinting in humans, since these distinct neurobehavioural disorders are both associated with genetic abnormalities (large deletions, uniparental disomy, and imprinting mutations) of inheritance in chromosome 15q11-q13, dependent on the parental origin (reviewed in ref. 1). Some AS patients have biparental inheritance, consistent with a single imprinted gene (active on the maternal chromosome), whereas similar PWS patients are not found suggesting that at least two imprinted genes (active on the paternal allele) may be necessary for classical PWS. We have previously shown that the small ribonucleoprotein associated protein SmN gene (SNRPN), located in the PWS critical region [2], is only expressed from the paternal allele and is differentially methylated on parental alleles [3]. Therefore, SNRPN may have a role in PWS. Methylation imprints have also been found at two other loci in 15q11-q13, PW71 [4] and D15S9 [5], which map 120 kb and 1.5 Mb proximal to SNRPN, respectively. We have now characterized in detail the gene structure and expression from two imprinted loci within 15q11-q13, SNRPN and D15S9, which suggests that both loci are surprisingly complex, with important implications for the pathogenesis of PWS.

scholarly journals Inhibition of MEK1/2 and GSK3 (2i system) affects blastocyst quality and early differentiation of porcine parthenotes

PeerJ ◽  
2019 ◽  
Vol 6 ◽  
pp. e5840 ◽  
Author(s):  
Jeongwoo Kwon ◽  
Ying-Hua Li ◽  
Yu-Jin Jo ◽  
YoungJin Oh ◽  
Suk Namgoong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glycogen Synthase ◽  
Epigenetic Modification ◽  
Mammalian Species ◽  
Embryonic Stem ◽  
Cell Number ◽  
Epigenetic Modifications ◽  
Related Gene ◽  
Developmental Potential ◽  
Blastocyst Quality

Inhibition of both MEK1/2 and glycogen synthase kinase-3 (GSK3; 2i system) facilitates the maintenance of naïve stemness for embryonic stem cells in various mammalian species. However, the effect of the inhibition of the 2i system on porcine early embryogenesis is unknown. We investigated the effect of the 2i system on early embryo development, expression of pluripotency-related genes, and epigenetic modifications. Inhibition of MEK1/2 (by PD0325901) and/or GSK3 (by CHIR99021) did not alter the developmental potential of porcine parthenogenetic embryos, but improved blastocyst quality, as judged by the blastocyst cell number, diameter, and reduction in the number of apoptotic cells. The expression levels of octamer-binding transcription factor 4 and SOX2, the primary transcription factors that maintain embryonic pluripotency, were significantly increased by 2i treatments. Epigenetic modification-related gene expression was altered upon 2i treatment. The collective results indicate that the 2i system in porcine embryos improved embryo developmental potential and blastocyst quality by regulating epigenetic modifications and pluripotency-related gene expression.

Genetic modification for bimaternal embryo development

2009 ◽  
Vol 21 (1) ◽  
pp. 31 ◽  
Author(s):  
Tomohiro Kono
Keyword(s):  
Embryo Development ◽  
Genetic Modification ◽  
Direct Evidence ◽  
Epigenetic Modification ◽  
Growth Period ◽  
Epigenetic Modifications ◽  
Imprinted Genes ◽  
Mammalian Development ◽  
Oocyte Growth ◽  
Paternal Contribution

Full mammalian development typically requires genomes from both the oocyte and spermatozoon. Biparental reproduction is necessary because of parent-specific epigenetic modification of the genome during gametogenesis; that is, a maternal methylation imprint imposed during the oocyte growth period and a paternal methylation imprint imposed in pregonadal gonocytes. This leads to unequivalent expression of imprinted genes from the maternal and paternal alleles in embryos and individuals. It is possible to hypothesise that the maternal methylation imprint is necessary to prevent parthenogenesis, which extinguishes the opportunity for having descendents, whereas the paternal methylation imprint prevents parthenogenesis, ensuring that a paternal contribution is obligatory for any descendants. To date, there are several lines of direct evidence that the epigenetic modifications that occur during oocyte growth have a decisive effect on mammalian development. Using bimaternal embryos with two sets of maternal genomes, the present paper illustrates how parental methylation imprints are an obstacle to the progression of parthenogenesis.

Developmental consequences of imprinting of parental chromosomes by DNA methylation

1990 ◽  
Vol 326 (1235) ◽  
pp. 313-327 ◽  
Keyword(s):  
Dna Methylation ◽  
Germ Line ◽  
Epigenetic Modifications ◽  
Parental Origin ◽  
Embryonic Cells ◽  
Maternal Transmission ◽  
Functional Differences ◽  
Selective Elimination ◽  
Allelic Differences ◽  
Female Genome

Genomic imprinting by epigenetic modifications, such as DNA methylation, confers functional differences on parental chromosomes during development so that neither the male nor the female genome is by itself totipotential. We propose that maternal chromosomes are needed at the time when embryonic cells are totipotential or pluripotential, but paternal chromosomes are probably required for the proliferation of progenitor cells of differentiated tissues. Selective elimination or proliferation of embryonic cells may occur if there is an imbalance in the parental origin of some alleles. The inheritance of repressed and derepressed chromatin structures probably constitutes the initial germ-line-dependent ‘imprints’. The subsequent modifications, such as changes in DNA methylation during early development, will be affected by the initial inheritance of epigenetic modifications and by the genotype-specific modifier genes. A significant number of transgene inserts are prone to reversible methylation imprinting so that paternally transmitted transgenes are undermethylated, whereas maternal transmission results in hypermethylation. Hence, allelic differences in epigenetic modifications can affect their potential for expression. The germ line evidently reverses the previously acquired epigenetic modifications before the introduction of new modifications. Errors in the reversal process could result in the transmission of epigenetic modifications to subsequent generation (s) with consequent cumulative phenotypic and grandparental effects.

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