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 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 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.

Influence of paternally imprinted genes on development

Development ◽  
1991 ◽  
Vol 113 (2) ◽  
pp. 679-687 ◽  
Author(s):  
S.C. Barton ◽  
A.C. Ferguson-Smith ◽  
R. Fundele ◽  
M.A. Surani
Keyword(s):  
Normal Development ◽  
Inner Cell Mass ◽  
Gene Dosage ◽  
Cell Mass ◽  
Characteristic Change ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Preferential Expression ◽  
The Brain ◽  
Anterior Posterior

The parental origin of chromosomes is critical for normal development in the mouse because some genes are imprinted resulting in a predetermined preferential expression of one of the alleles. Duplication of the paternal (AG: androgenones) or maternal (GG/PG: gynogenones/parthenogenones) genomes will result in an excess or deficiency of gene dosage with corresponding phenotypic effects. Here, we report on the effects of paternally imprinted genes on development following introduction of the AG inner cell mass into normal blastocysts. There was a striking increase in embryonic growth by up to 50%, and a characteristic change in embryonic shape, partly because of the corresponding increase in length of the anterior-posterior axis. These changes, between e12-e15, were proportional to the contribution from AG cells to the embryo. However, a contribution of AG cells in excess of 50% was invariably lethal as development progressed to e15. A limited number of chimeras were capable of full-term development provided there was a relatively low contribution from AG cells. The distribution of AG cells in chimeras was not uniform, especially later in development when there was a disproportionate presence of AG cells in the mesodermally derived tissues. Their contribution was consistently greater in the heart and skeletal muscle, but was considerably lower in the brain. Chimeras detected after birth were either dead or developed severe abnormalities of the skeletal elements, particularly of the ribs which were enlarged, distorted and fused, with greatly increased cartilaginous material with an absence of normal ossification. These phenotypic effects in chimeras are reciprocal to those observed in the presence of GG/PG cells, which resulted in a substantial size reduction approaching 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

scholarly journals Transgenic Mice

2000 ◽  
Vol 11 (suppl 2) ◽  
pp. S88-S94 ◽  
Author(s):  
CHARLES BABINET
Keyword(s):  
Animal Models ◽  
Transgenic Mice ◽  
Gene Function ◽  
Genetic Information ◽  
Mouse Genome ◽  
Normal Development ◽  
Genetic Diseases ◽  
Gene Replacement ◽  
Mammalian Development ◽  
The Creation

Abstract. Stable integration into the mouse genome of exogenous genetic information, i.e., the creation of transgenic mice, has become a privileged way of analyzing gene function in normal development and pathology. Both gene addition and gene replacement may be performed. This has allowed, in particular, the creation of mice in which precise mutations are introduced into a given gene. Furthermore, in recent years, strategies that induce the expression of a mutation in a given type of cell and/or at a given time in development have been developed. Thus, the transgenic methodology affords a unique and irreplaceable tool for the study of mammalian development and biology and for the creation of animal models for human genetic diseases.

scholarly journals Genomic imprinting and cancer: Remembering the parental origin

2010 ◽  
Vol 32 (5) ◽  
pp. 26-29
Author(s):  
Adele Murrell ◽  
Santiago Uribe-Lewis
Keyword(s):  
Dna Methylation ◽  
Genomic Imprinting ◽  
Histone Modifications ◽  
Germ Cells ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Parental Allele ◽  
Paternal Line ◽  
Specific Manner ◽  
Parental Copy

Genomic imprinting results in only one copy of a diploid pair of alleles being expressed in a parentof-origin-specific manner. The ‘imprint’ encodes a memory of whether a gene came through the maternal or paternal line and contains the information that decides which parental copy will be active or silent. Imprints are established in the developing gametes, passed on to the next generation after fertilization where they are read and maintained in the somatic cells or erased and reset in the germ cells. The components of the ‘memory’ are a combination of epigenetic features such as DNA methylation, post-translational histone modifications and protein/RNA factors that can bind to DNA and label the genes such that a cell's transcription machinery can distinguish between maternal and paternal alleles. Most imprinted genes are associated with sequences that are methylated on only one parental allele, known as differentially methylated regions (DMRs).

scholarly journals A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Hannah Demond ◽  
Zahra Anvar ◽  
Bahia Namavar Jahromi ◽  
Angela Sparago ◽  
Ankit Verma ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Hydatidiform Mole ◽  
Human Oocyte ◽  
Imprinted Genes ◽  
High Coverage ◽  
Genome Wide ◽  
A Genome ◽  
Mechanistic Basis ◽  
Methylation Defects

Abstract Background Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses: in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. The rarity of these disorders and the possibility that methylation defects originate in oocytes have made these questions very challenging to address. Methods Single-cell bisulphite sequencing (scBS-seq) was used to assess methylation in oocytes from a patient with BiCHM identified to be homozygous for an inactivating mutation in the human SCMC component KHDC3L. Genome-wide methylation analysis of a preimplantation embryo and molar tissue from the same patient was also performed. Results High-coverage scBS-seq libraries were obtained from five KHDC3Lc.1A>G oocytes, which revealed a genome-wide deficit of DNA methylation compared with normal human oocytes. Importantly, germline differentially methylated regions (gDMRs) of imprinted genes were affected similarly to other sequence features that normally become methylated in oocytes, indicating no selectivity towards imprinted genes. A range of methylation losses was observed across genomic features, including gDMRs, indicating variable sensitivity to defects in the SCMC. Genome-wide analysis of a pre-implantation embryo and molar tissue from the same patient showed that following fertilisation methylation defects at imprinted genes persist, while most non-imprinted regions of the genome recover near-normal methylation post-implantation. Conclusions We show for the first time that the integrity of the SCMC is essential for de novo methylation in the female germline. These findings have important implications for understanding the role of the SCMC in DNA methylation and for the origin of imprinting defects, for counselling affected families, and will help inform future therapeutic approaches.

scholarly journals Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes

Reproduction ◽  
2011 ◽  
Vol 141 (2) ◽  
pp. 207-216 ◽  
Author(s):  
Christelle Stouder ◽  
Ariane Paoloni-Giacobino
Keyword(s):  
Adult Male ◽  
Endocrine Disrupting Chemicals ◽  
Methylation Pattern ◽  
Imprinted Genes ◽  
Male Mice ◽  
Systematic Analysis ◽  
Adult Mice ◽  
Male Gametes ◽  
Pregnant Mice ◽  
Methylation Defects

Endocrine-disrupting chemicals (EDCs), among which methoxychlor (MXC), have been reported to affect the male reproductive system. This study evaluates the possible deleterious effects of MXC on imprinted genes. After administration of the chemical in adult male mice or in pregnant mice we analyzed by pyrosequencing possible methylation defects in two paternally imprinted (H19 and Meg3 (Gtl2)) and three maternally imprinted (Mest (Peg1), Snrpn, and Peg3) genes in the sperm and in the tail, liver, and skeletal muscle DNAs of the adult male mice and of the male offspring. MXC treatment of adult mice decreased the percentages of methylated CpGs of Meg3 and increased those of Mest, Snrpn, and Peg3 in the sperm DNA. MXC treatment of pregnant mice decreased the mean sperm concentrations by 30% and altered the methylation pattern of all the imprinted genes tested in the F1 offspring. In the latter case, MXC effects were transgenerational but disappeared gradually from F1 to F3. MXC did not affect imprinting in the somatic cells, suggesting that it exerts its damaging effects via the process of reprogramming that is unique to gamete development. A systematic analysis at the CpG level showed a heterogeneity in the CpG sensitivity to MXC. This observation suggests that not only DNA methylation but also other epigenetic modifications can explain the transgenerational effects of MXC. The reported effects of EDCs on human male spermatogenesis might be mediated by complex imprinting alterations analogous to those described in this study.

scholarly journals Genomic imprinting in germ cells: imprints are under control

Reproduction ◽  
2010 ◽  
Vol 140 (3) ◽  
pp. 411-423 ◽  
Author(s):  
Philippe Arnaud
Keyword(s):  
Dna Methylation ◽  
Genomic Imprinting ◽  
Germ Cells ◽  
Imprinted Genes ◽  
Regulatory Sequences ◽  
Sequence Specificity ◽  
Maternal Allele ◽  
Primary Sequence ◽  
Chromatin Configuration

The cis-acting regulatory sequences of imprinted gene loci, called imprinting control regions (ICRs), acquire specific imprint marks in germ cells, including DNA methylation. These epigenetic imprints ensure that imprinted genes are expressed exclusively from either the paternal or the maternal allele in offspring. The last few years have witnessed a rapid increase in studies on how and when ICRs become marked by and subsequently maintain such epigenetic modifications. These novel findings are summarised in this review, which focuses on the germline acquisition of DNA methylation imprints and particularly on the combined role of primary sequence specificity, chromatin configuration, non-histone proteins and transcriptional events.

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