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W Reik

Publications and source records attributed to W Reik.

At least 91 records · Page 5Linked to original sources
PubMed1993

Age at onset in Huntington's disease and methylation at D4S95.

Age at onset in Huntington's disease (HD) is variable and is influenced by parental sex, paternal age, and genetic background. Several recent models have tried to explain this variable expressivity by invoking parental imprinting and related aspects of epigenetic inheritance. Some of these mechanisms may result in variable DNA methylation at or near the HD gene. We show here that methylation at D4S95, a locus tightly linked to the HD gene, is highly variable. A comparison between patients with early onset HD, late onset HD, and normal controls showed no significant correlation between methylation and age at onset. However, we found a significant association of the age of the patient with demethylation at D4S95. Older persons tend to have lower levels of methylation at this locus. This observation is of interest with regard to studies that show an effect of paternal age, or more generally of 'ageing genes', on age at onset in HD.

Adolescent↗
PubMed1993

Adult phenotype in the mouse can be affected by epigenetic events in the early embryo.

Major epigenetic modifications apparently occur during early development in the mouse. The factors that induce such modifications are complex and may involve the various components of a zygote. We have started to explore whether changes in the nucleocytoplasmic composition brought about by micromanipulation can induce phenotypic effects through epigenetic modifications. Nucleocytoplasmic hybrids were therefore prepared by transplanting a female pronucleus into a recipient egg from a different genotype. As a result, the maternal genome was of a different genetic background as compared with the egg cytoplasm. Specifically, experimental zygotes had cytoplasm from the inbred strain C57BL/6, a maternal genome from DBA/2, and a paternal genome from C57BL/6 (termed BDB hybrids). The mirror-image combination, termed DBD, was also made. The reconstituted zygotes were transferred to recipients and allowed to develop to term. Mice born from manipulated zygotes showed transcriptional repression and DNA methylation of major urinary protein genes in their liver, as well as growth deficiency resulting in reduced adult body weight. No altered phenotype was observed in controls in which the maternal pronucleus was simply transplanted back into another zygote of the same genetic background. These results clearly demonstrate phenotypic as well as molecular effects on DNA methylation and expression of at least one gene. Phenotype was therefore no longer predicted by genotype as a result of epigenetic modifications in experimental embryos. What precisely triggers the phenotypic and epigenetic changes is unknown, but presumably, nucleocytoplasmic interactions in hybrid zygotes may be partly responsible.

Animals↗
PubMed1992

Mapping of a mouse homolog of a heterochromatin protein gene the X chromosome.

Modifiers of position-effect-variegation in Drosophila are thought to encode proteins that are either structural components of heterochromatin or enzymes that modify these components. We have recently shown that a sequence motif found in one Drosophila modifier gene, Heterochromatin protein 1 (HP1), is conserved in a wide variety of animal and plant species (Singh et al. 1991). Using this motif, termed chromo box, we have cloned a mouse candidate modifier gene, M31, that also shows considerable sequence homology to Drosophila HP1. Here we report evidence of at least four independently segregating loci in the mouse homologous to the M31 cDNA. One of these loci--Cbx-rs1--maps to the X Chromosome (Chr), 1 cM proximal to Amg and outside the X-inactivation center region.

Animals↗
PubMed1992

Parental imprinting: potentially active chromatin of the repressed maternal allele of the mouse insulin-like growth factor II (Igf2) gene.

The mouse insulin-like growth factor II (Igf2) gene, which is located on distal chromosome 7 (Chr7), has been shown previously to undergo tissue-specific parental imprinting. This imprinting results in expression of Igf2 from the paternally inherited chromosome and repression of the maternally inherited allele in most tissues of the developing embryo. We are using embryos with the maternal duplication and paternal deficiency of distal Chr7 to characterize the mechanism that underlies repression of the maternal allele. We show that the chromatin of the 5' region of the repressed Igf2 allele is potentially active for transcription rather than heterochromatic. In particular, a CpG island that comprises one of the two strong promoters is unmethylated at both parental alleles, and DNase I hypersensitive sites in and around the strong promoters are consistently present on both parental chromosomes. In agreement with the chromatin state, primary transcripts from the maternal Igf2 allele have been detected at low but significant levels. These findings differ from observations in other instances of imprinting, namely, X-chromosome inactivation and transgene imprinting in mice. Although no parent-specific differences were detected in either DNA methylation or sensitivity to nucleases at these promoters, we have observed parental methylation differences in a region several kilobases upstream of the first exon. The differential activity of the parental Igf2 alleles could be achieved through epigenetic modifications situated outside the promoters or by subtle and yet unidentified modifications at the promoters.

Alleles↗
PubMed1991

Methylation levels of maternal and paternal genomes during preimplantation development.

The methylation status of three highly repeated sequences was studied in sperm, eggs and preimplantation embryos with different combinations of parental chromosomes. High levels of methylation of the IAP and MUP sequence families were found in sperm and in eggs, whereas the L1 repeat was found to be highly methylated in sperm but only about 42% methylated in eggs. To assess how the two parental genomes behaved during preimplantation development, normal, fertilised embryos were compared with parthenogenetic embryos where the chromosomes are exclusively of maternal origin. It was observed that the high levels of methylation at the IAP and MUP sequences were retained through early development, with the first signs of demethylation at the IAP sequences apparent on both parental chromosomes in the blastocyst. Methylation at the sperm-derived L1 sequences dropped to about the same level as that of the egg-derived sequences by the late 2-cell stage, both then remain at this intermediate level until around the time of cavitation when levels fell to about 10% in the blastocyst. High levels of DNA methylase were detected in germinal vesicle and metaphase II oocytes; these high levels were maintained in fertilised and parthenogenetic embryos through into the morula and then declined to be undetectable in the blastocyst. Our comparison of maternal and paternal genomes suggests that methylation levels at repeat sequences are remarkably similar at the time of fertilisation or, as in the case of the L1 sequences, they become so during the first few cell cycles. Hence, there do not appear to be global methylation differences between the genomes that are retained through preimplantation development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Developmental consequences of imprinting of parental chromosomes by DNA methylation.

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.

Animals↗
PubMed1990

Imprinting by DNA methylation: from transgenes to endogenous gene sequences.

A number of transgenes in the mouse show variation in methylation and expression phenotypes dependent on parental transmission. It appears that there exist at least two types of transgene imprinting; one is retained on an essentially homozygous background, while the other requires heterozygosity at some modifying loci in the genome and is observed as differences in phenotype in reciprocal crosses. For this type of imprinting to occur, the parental origin of the modifier locus itself is important, and parental asymmetry may involve specific interactions between egg cytoplasm and the chromosomes. Based on the identification of 'methylation polymorphism' in the mouse genome, we also show that endogenous gene sequences can undergo imprinting by DNA methylation.

Animals↗
PubMed1990

Genomic imprinting and cancer.

Genomic imprinting results in a functional non-equivalence of parental chromosomes, presumably by epigenetic modification of the genome, and is required for normal mammalian development. In general, reciprocal phenotypes are observed in embryos containing alterations in the dosage of parental chromosomes, for example where both copies of chromosomes or chromosomal regions are derived from one parent. These phenotypes indicate that duplications of maternal chromosomes inhibit embryonic growth and proliferation whereas duplications of the paternal genome result in enhanced cell growth and proliferation. Alterations in the dosage of parental chromosomes have recently been observed in some forms of recessive tumour in man. Here we discuss the role and possible mechanisms of genomic imprinting during embryogenesis and attempt to draw parallels between the parental origin of the loss of heterozygosity observed in some human tumours and the developmental phenotypes that arise in mice with similar distortions of parental origin. These observations strongly implicate genomic imprinting in the genesis of some forms of tumour and, more generally, in the genetic predisposition to cancer.

Animals↗
PubMed1989

Genomic imprinting and genetic disorders in man.

In a considerable number of genetic disorders in the human, the phenotypic expression of the disease can depend on maternal or paternal inheritance of the mutation. It is suggested that genomic imprinting, an epigenetic process that marks maternal and paternal chromosomes in mammals, is involved in such parental effects.

Animals↗
PubMed1989

Systematic elimination of parthenogenetic cells in mouse chimeras.

The developmental potential of primitive ectoderm cells lacking paternal chromosomes was investigated by examining the distribution of parthenogenetic cells in chimeras. Using GPI-1 allozymes as marker, parthenogenetic cells were detected in most organs and tissues in adult chimeras. However, these cells were under severe selective pressure compared with cells from normal fertilized embryos. In the majority of chimeras, parthenogenetic cells in individual animals were observed in a limited number of tissues and organs and, even in these instances, their contribution was substantially reduced. Nevertheless, parthenogenetic cells were detected more consistently in some organs, especially the brain, heart, kidney and spleen. In contrast, there was apparently a systematic selection against parthenogenetic cells in some tissues, most notably in skeletal muscle, liver and pancreas. These results suggest that paternally derived genes are probably required not only for the development of extraembryonic structures but also for subsequent development of embryonic tissues derived from the primitive ectoderm lineage.

Animals↗
PubMed1988

Transgenes as probes for active chromosomal domains in mouse development.

Embryonic development entails a well defined temporal and spatial programme of gene expression, which may be influenced by active chromosomal domains. These chromosomal domains can be detected using transgenes which integrate randomly throughout the genome, as their expression can be affected by chromosomal position. Position effects are probably exerted most strongly on transgenes that do not contain strong promoters, enhancers or other modulating sequences. Here we have systematically explored position effects using a transgene with the weak herpes-simplex-virus thymidine-kinase promoter, linked to the readily visualized lacZ indicator gene (HSV-TK-lacZ). Each transgenic fetus with detectable expression displayed a unique lacZ staining pattern. Thus expression of this construct is apparently dictated entirely by its chromosomal position, without any construct specificity. Furthermore the transgene is faithfully transmitted to subsequent generations, allowing for systematic mapping of changes in expression during development and in adult life. These results demonstrate that transgenes can indeed be powerful tools to probe the genome for active chromosomal regions, with the potential for identifying endogenous genes involved in organogenesis and pattern formation.

Animals↗