Mechanism of imprinting on mouse distal chromosome 7

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.

Download Full-text

The inheritance of germline-specific epigenetic modifications during development

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1993.0013 ◽

1993 ◽

Vol 339 (1288) ◽

pp. 165-172 ◽

Cited By ~ 14

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.

Download Full-text

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

Molecular and Cellular Biology ◽

10.1128/mcb.24.9.3588-3595.2004 ◽

2004 ◽

Vol 24 (9) ◽

pp. 3588-3595 ◽

Cited By ~ 29

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.

Download Full-text

Mouse embryos with paternal duplication of an imprinted chromosome 7 region die at midgestation and lack placental spongiotrophoblast

Development ◽

10.1242/dev.122.1.265 ◽

1996 ◽

Vol 122 (1) ◽

pp. 265-270 ◽

Cited By ~ 3

Author(s):

K.J. McLaughlin ◽

P. Szabo ◽

H. Haegel ◽

J.R. Mann

Keyword(s):

Mouse Embryos ◽

Chromosome 7 ◽

Imprinted Genes ◽

Uniparental Inheritance ◽

Aberrant Expression ◽

Distal Chromosome ◽

Specific Activities ◽

Androgenetic Embryos ◽

Genomic Regions ◽

Chromosome Regions

Imprinted genomic regions have been defined by the production of mice with uniparental inheritance or duplication of homologous chromosome regions. With most of the genome investigated, paternal duplication of only distal chromosomes 7 and 12 results in the lack of offspring, and prenatal lethality is presumed. Aberrant expression of imprinted genes in these two autosomal regions is therefore strongly implicated in the periimplantation lethality of androgenetic embryos. We report that mouse embryos with paternal duplication of distal chromosome 7 (PatDup.d7) die at midgestation and lack placental spongiotrophoblast. Thus, the much earlier death of androgenones must involve paternal duplication of other autosomal regions, acting independently of or synergistically with PatDup.d7. The phenotype observed is similar, if not identical to, that resulting from mutation of the imprinted distal chromosome 7 gene, Mash2, which in normal midgestation embryos exhibits spongiotrophoblast-specific maternally active/paternally inactive (m+/p-) allelic expression. Thus, the simplest explanation for the PatDup.d7 phenotype is p-/p- expression of this gene. We also confirm that PatDup.d7 embryos lack H19 RNA and posses excess Igf2 RNA as might be expected from the parental-specific activities of these genes in normal embryos.

Download Full-text

Multiple Mechanisms Regulate Imprinting of the Mouse Distal Chromosome 7 Gene Cluster

Molecular and Cellular Biology ◽

10.1128/mcb.18.6.3466 ◽

1998 ◽

Vol 18 (6) ◽

pp. 3466-3474 ◽

Cited By ~ 147

Author(s):

Tamara Caspary ◽

Michele A. Cleary ◽

Catherine C. Baker ◽

Xiao-Juan Guan ◽

Shirley M. Tilghman

Keyword(s):

Dna Methylation ◽

Gene Cluster ◽

Genomic Imprinting ◽

Dna Methyltransferase ◽

Regulatory Elements ◽

Chromosome 7 ◽

Imprinted Genes ◽

Global Regulator ◽

Loss Of Imprinting ◽

Distal Chromosome

ABSTRACT Genomic imprinting is an epigenetic process that results in the preferential silencing of one of the two parental copies of a gene. Although the precise mechanisms by which genomic imprinting occurs are unknown, the tendency of imprinted genes to exist in chromosomal clusters suggests long-range regulation through shared regulatory elements. We characterize a 800-kb region on the distal end of mouse chromosome 7 that contains a cluster of four maternally expressed genes, H19, Mash2, Kvlqt1, andp57Kip2 , as well as two paternally expressed genes, Igf2 and Ins2, and assess the expression and imprinting of Mash2, Kvlqt1, andp57Kip2 during development in embryonic and extraembryonic tissues. Unlike Igf2 and Ins2, which depend on H19 for their imprinting,Mash2, p57Kip2 , andKvlqt1 are unaffected by a deletion of the H19gene region, suggesting that these more telomeric genes are not regulated by the mechanism that controls H19,Igf2, and Ins2. Mutations in humanp57Kip2 have been implicated in Beckwith-Wiedemann syndrome, a disease that has also been associated with loss of imprinting of IGF2. We find, however, that a deletion of the gene has no effect on imprinting within the cluster. Surprisingly, the three maternally expressed genes are regulated very differently by DNA methylation; p57Kip2 is activated, Kvlqt1 is silenced, and Mash2 is unaffected in mice lacking DNA methyltransferase. We conclude thatH19 is not a global regulator of imprinting on distal chromosome 7 and that the telomeric genes are imprinted by a separate mechanism(s).

Download Full-text

Parental Imprinting on Mouse Chromosome 7

Acta geneticae medicae et gemellologiae twin research ◽

10.1017/s0001566000001070 ◽

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.

Download Full-text

G9a Histone Methyltransferase Contributes to Imprinting in the Mouse Placenta

Molecular and Cellular Biology ◽

10.1128/mcb.01111-07 ◽

2007 ◽

Vol 28 (3) ◽

pp. 1104-1113 ◽

Cited By ~ 121

Author(s):

Alexandre Wagschal ◽

Heidi G. Sutherland ◽

Kathryn Woodfine ◽

Amandine Henckel ◽

Karim Chebli ◽

...

Keyword(s):

Dna Methylation ◽

Histone Methylation ◽

Histone Methyltransferase ◽

Chromosome 7 ◽

Gene Repression ◽

Imprinted Genes ◽

Set Domain ◽

Imprinted Gene ◽

Mouse Placenta ◽

Distal Chromosome

ABSTRACT Whereas DNA methylation is essential for genomic imprinting, the importance of histone methylation in the allelic expression of imprinted genes is unclear. Imprinting control regions (ICRs), however, are marked by histone H3-K9 methylation on their DNA-methylated allele. In the placenta, the paternal silencing along the Kcnq1 domain on distal chromosome 7 also correlates with the presence of H3-K9 methylation, but imprinted repression at these genes is maintained independently of DNA methylation. To explore which histone methyltransferase (HMT) could mediate the allelic H3-K9 methylation on distal chromosome 7, and at ICRs, we generated mouse conceptuses deficient for the SET domain protein G9a. We found that in the embryo and placenta, the differential DNA methylation at ICRs and imprinted genes is maintained in the absence of G9a. Accordingly, in embryos, imprinted gene expression was unchanged at the domains analyzed, in spite of a global loss of H3-K9 dimethylation (H3K9me2). In contrast, the placenta-specific imprinting of genes on distal chromosome 7 is impaired in the absence of G9a, and this correlates with reduced levels of H3K9me2 and H3K9me3. These findings provide the first evidence for the involvement of an HMT and suggest that histone methylation contributes to imprinted gene repression in the trophoblast.

Download Full-text

A hobo Transgene That Encodes the P-Element Transposase in Drosophila melanogaster: Autoregulation and Cytotype Control of Transposase Activity

Genetics ◽

10.1093/genetics/161.1.195 ◽

2002 ◽

Vol 161 (1) ◽

pp. 195-204 ◽

Cited By ~ 1

Author(s):

Michael J Simmons ◽

Kevin J Haley ◽

Craig D Grimes ◽

John D Raymond ◽

Jarad B Niemi

Keyword(s):

Drosophila Melanogaster ◽

Gonadal Dysgenesis ◽

P Element ◽

Hsp70 Gene ◽

Alternate Splicing ◽

Male And Female ◽

P Elements ◽

Male Germline ◽

Female Germline ◽

Transposase Expression

Abstract Drosophila were genetically transformed with a hobo transgene that contains a terminally truncated but otherwise complete P element fused to the promoter from the Drosophila hsp70 gene. Insertions of this H(hsp/CP) transgene on either of the major autosomes produced the P transposase in both the male and female germlines, but not in the soma. Heat-shock treatments significantly increased transposase activity in the female germline; in the male germline, these treatments had little effect. The transposase activity of two insertions of the H(hsp/CP) transgene was not significantly greater than their separate activities, and one insertion of this transgene reduced the transposase activity of P(ry+, Δ2-3)99B, a stable P transgene, in the germline as well as in the soma. These observations suggest that, through alternate splicing, the H(hsp/CP) transgene produces a repressor that feeds back negatively to regulate transposase expression or function in both the somatic and germline tissues. The H(hsp/CP) transgenes are able to induce gonadal dysgenesis when the transposase they encode has P-element targets to attack. However, this ability and the ability to induce P-element excisions are repressed by the P cytotype, a chromosomal/cytoplasmic state that regulates P elements in the germline.

Download Full-text

Molecular Analysis of Nondisjunction in Mice Heterozygous for a Robertsonian Translocation

Genetics ◽

10.1093/genetics/161.3.1219 ◽

2002 ◽

Vol 161 (3) ◽

pp. 1219-1224

Author(s):

Lara A Underkoffler ◽

Laura E Mitchell ◽

A Russell Localio ◽

Shannon M Marchegiani ◽

Justin Morabito ◽

...

Keyword(s):

Molecular Analysis ◽

Robertsonian Translocation ◽

Metacentric Chromosome ◽

Paternal Age ◽

Chromosome 7 ◽

Parental Origin ◽

Molecular Genotyping ◽

Factors Influencing ◽

Meiotic Nondisjunction ◽

Acrocentric Chromosomes

Abstract A Robertsonian translocation results in a metacentric chromosome produced by the fusion of two acrocentric chromosomes. Rb heterozygous mice frequently generate aneuploid gametes and embryos, providing a good model for studying meiotic nondisjunction. We intercrossed mice heterozygous for a (7.18) Robertsonian translocation and performed molecular genotyping of 1812 embryos from 364 litters with known parental origin, strain, and age. Nondisjunction events were scored and factors influencing the frequency of nondisjunction involving chromosomes 7 and 18 were examined. We concluded the following: The frequency of nondisjunction among 1784 embryos (3568 meioses) was 15.9%.Nondisjunction events were distributed nonrandomly among progeny. This was inferred from the distribution of the frequency of trisomics and uniparental disomics (UPDs) among all litters.There was no evidence to show an effect of maternal or paternal age on the frequency of nondisjunction.Strain background did not play an appreciable role in nondisjunction frequency.The frequency of nondisjunction for chromosome 18 was significantly higher than that for chromosome 7 in males.The frequency of nondisjunction for chromosome 7 was significantly higher in females than in males. These results show that molecular genotyping provides a valuable tool for understanding factors influencing meiotic nondisjunction in mammals.

Download Full-text

Genomic imprinting and its role in ethiology of human hereditary diseases

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2004-3-8-17 ◽

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.

Download Full-text

piRNA and Transposon Dynamics in Drosophila: A Female Story

Genome Biology and Evolution ◽

10.1093/gbe/evaa094 ◽

2020 ◽

Vol 12 (6) ◽

pp. 931-947 ◽

Cited By ~ 2

Author(s):

Bastien Saint-Leandre ◽

Pierre Capy ◽

Aurelie Hua-Van ◽

Jonathan Filée

Keyword(s):

Small Rna ◽

Drosophila Simulans ◽

Genomic Context ◽

Genome Sequences ◽

Genomic Features ◽

Male Germline ◽

Recent Activity ◽

Pirna Pathway ◽

Female Germline ◽

The Relationship

Abstract The germlines of metazoans contain transposable elements (TEs) causing genetic instability and affecting fitness. To protect the germline from TE activity, gonads of metazoans produce TE-derived PIWI-interacting RNAs (piRNAs) that silence TE expression. In Drosophila, our understanding of piRNA biogenesis is mainly based on studies of the Drosophila melanogaster female germline. However, it is not known whether piRNA functions are also important in the male germline or whether and how piRNAs are affected by the global genomic context. To address these questions, we compared genome sequences, transcriptomes, and small RNA libraries extracted from entire testes and ovaries of two sister species: D. melanogaster and Drosophila simulans. We found that most TE-derived piRNAs were produced in ovaries and that piRNA pathway genes were strongly overexpressed in ovaries compared with testes, indicating that the silencing of TEs by the piRNA pathway mainly took place in the female germline. To study the relationship between host piRNAs and TE landscape, we analyzed TE genomic features and how they correlate with piRNA production in the two species. In D. melanogaster, we found that TE-derived piRNAs target recently active TEs. In contrast, although Drosophila simulans TEs do not display any features of recent activity, the host still intensively produced silencing piRNAs targeting old TE relics. Together, our results show that the piRNA silencing response mainly takes place in Drosophila ovaries and indicate that the host piRNA response is implemented following a burst of TE activity and could persist long after the extinction of active TE families.

Download Full-text