Aging of Xenopus tropicalis Eggs Leads to Deadenylation of a Specific Set of Maternal mRNAs and Loss of Developmental Potential

As first shown more than 100 years ago, fertilization of an aged (overripe) egg increases the rate of malformations and embryonic loss in several vertebrates, including possibly humans as well. Since the molecular events in aging eggs may be similar in these species, we established in the frog Xenopus tropicalis a defined protocol for delayed fertilization of eggs. A three-hour delayed fertilization led to a dramatic increase in malformation and mortality. Gene expression profiling revealed that 14% of the polyadenylated maternal transcripts were downregulated upon aging. These transcripts were not degraded, but rather deadenylated as shown for specific maternal mRNAs. The affected transcripts are characterized by a relatively short 3′UTR and a paucity of cytoplasmic polyadenylation elements (CPE) and polyadenylation signals (PAS). Furthermore, maternal mRNAs known to be deadenylated during egg maturation as well as after fertilization were preferentially deadenylated in aged eggs. Taken together our analysis of aging eggs reveals that unfertilized eggs are in a dynamic state that was previously not realized. On the one hand deadenylation of transcripts that are typically deadenylated during egg maturation continues and this implies overripeness of the aged egg in the truest sense of the word. On the other hand transcripts that normally are deadenylated after fertilization loose their poly(A) in the aged egg and this implies that the egg awaiting fertilization starts processes that are normally only observed after fertilization. Based on our novel finding we postulate that the imbalance of the polyadenylated maternal transcripts upon egg aging contributes to the loss of developmental potential. Based on this hypothesis the developmental consequences of downregulation of specific transcripts can be analyzed in future

Detection of aberrant DNA methylation in unique Prader — Willi syndrome patients and its diagnostic implications

Most patients with Prader - Willi syndrome have a deletion of 15q11 - 13 or maternal uniparental disomy for chromosome 15. The shortest region of deletion overlap is presently defined by the gene for the small nuclear ribonucleoprotein N (SNRPN). We have investigated the integrity of SNRPN as well as the methylation status of D15S63 (PW71) in two patients with apparently normal chromosomes 15 of biparental origin. SNRPN is normal in one patient and deleted in the other one. Both patients are intact at the D15S63 locus, but have an abnormal methylation pattern. These results suggest that a DNA sequence close to SNRPN determines the methylation status of D15S63 and that the methylation test does not only detect the common deletions and uniparental disomy, but other rare lesions as wel

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Molecular definition of the Prader — Willi syndrome chromosome region and orientation of the SNRPN gene

The Prader—Willi syndrome and the Angelman syndrome are caused by the loss of function of distinct but closely linked genes on human chromosome 15. Based on a yeast artificial chromosome restriction map and two key patients we have determined that the shortest region of deletion overlap in the Prader—Willi syndrome comprises 320 kb. The region Includes the anonymous DNA marker PW71 (D15S63) and the gene for the small nuclear ribonucleoprotein N (SNRPN). The SNRPN gene maps 130 kb distal to PW71 and is transcribed from centromere to telomer

Modification of 15q11 — q13 DNA methylation imprints in unique Angelman and Prader — Willi patients

The clearest example of genomic Imprinting in humans comes from studies of the Angelman (AS) and Prader—Wil (PWS) syndromes. Although these are clinically distinct disorders, both typically result from a loss of the same chromosomal region, 15q11 - q13. AS usually results from either a maternal deletion of this region, or paternal uniparental disomy (UPD; both chromosomes 15 Inherited from the father). PWS results from paternal deletion of 15q11 - q13 or maternal UPD of chromosome 15. We have recently described a parent-specific DNA methylation imprint in a gene at the D15S9 locus (new gene symbol, ZNF 127), within the 15q11 - q13 region, that identifies AS and PWS patients with either a deletion or UPD. Here we describe an AS sibship and three PWS patients in which chromosome 15 rearrangements alter the methylation state at ZNF127, even though this locus is not directly involved in the rearrangement. Parent-specific DNA methylation imprints are also altered at ZNF127 and D15S63 (another locus with a parent-specific methylation imprint) in an AS sibship which have no detectable deletion or UPD of chromosome 15. These unique patients may provide insight into the imprinting process that occurs in proximal chromosome 15 in human

An Alu Element–Associated Hypermethylation Variant of the POMC Gene Is Associated with Childhood Obesity

The individual risk for common diseases not only depends on genetic but also on epigenetic polymorphisms. To assess the role of epigenetic variations in the individual risk for obesity, we have determined the methylation status of two CpG islands at the POMC locus in obese and normal-weight children. We found a hypermethylation variant targeting individual CpGs at the intron2–exon3 boundary of the POMC gene by bisulphite sequencing that was significantly associated with obesity. POMC exon3 hypermethylation interferes with binding of the transcription enhancer P300 and reduces expression of the POMC transcript. Since intron2 contains Alu elements that are known to influence methylation in their genomic vicinity, the exon3 methylation variant seems to result from an Alu element–triggered default state of methylation boundary definition. Exon3 hypermethylation in the POMC locus represents the first identified DNA methylation variant that is associated with the individual risk for obesity