Biomedical subjects

Timothy H Bestor

Publications and source records attributed to Timothy H Bestor.

22 records · Page 2Linked to original sources

PubMed2002

Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) presents with visceromegaly, macroglossia, tumor predisposition and other congenital abnormalities, and is usually associated with abnormalities of chromosome 11p15. A number of identical twin pairs, mostly female, have been reported to be discordant for BWS. We show here that the incidence of female monozygotic twins among patients with BWS is dramatically increased over that of the general population. A cluster of imprinted genes within 11p15 is thought to be coordinately regulated via the imprinted expression of KCNQ1OT1, which encodes an untranslated RNA. In skin fibroblasts from five monozygotic twin pairs discordant for BWS, each affected twin had an imprinting defect at KCNQ1OT1 on 11p15, whereas the unaffected twin did not. Five additional monozygotic twin pairs, for whom only blood was available, also displayed an imprinting defect at KCNQ1OT1. It is possible that discordance for BWS in MZ twins is due to unequal splitting of the inner cell mass during twinning, thereby causing differential maintenance of imprinting at KCNQ1OT1. Alternatively, we propose that KCNQ1OT1 is especially vulnerable to a loss of imprinting event, caused by a lack of maintenance DNA methylation at a critical stage of preimplantation development, and that this loss of imprinting predisposes to twinning as well as to discordance for BWS. These data underscore the importance of continued surveillance of children born following assisted reproductive technologies that impact the preimplantation embryo.

Beckwith-Wiedemann Syndrome↗

PubMed2002

Helicase homologues maintain cytosine methylation in plants and mammals.

The Arabidopsis DDM1 gene is required for the maintenance of genomic methylation patterns but is a helicase homolog of the SWI2/SNF2 family rather than a DNA methyltransferase. Dennis et al. have shown that disruption of the mouse Lsh gene, the mammalian gene most closely related to DDM1, causes demethylation of the mouse genome. This result suggests that the mechanisms that maintain methylation patterns in the genomes of mammals and flowering plants are more conserved than previously suspected.

Animals↗

PubMed2002

Methylation dynamics of imprinted genes in mouse germ cells.

DNA methylation differences between maternal and paternal alleles of many imprinted genes are inherited from the male and female gametes and subsequently maintained during development. However, the stages of gametogenesis during which methylation imprints are established have not been well defined. In this study, we used bisulfite sequencing to determine the methylation dynamics of the imprinted genes small nuclear ribonucleoprotein N (Snrpn), insulin-like growth factor 2 receptor (Igf2r), mesoderm-specific transcript (Mest; formerly Peg1), paternally expressed gene 3 (Peg3), and H19 fetal liver mRNA (H19). We identified regions in the maternally imprinted genes (Snrpn, Mest, and Peg3) that were unmethylated in sperm but 100% methylated in mature oocytes. Igf2r, which is expressed from the maternal allele, was completely methylated within intronic differentially methylated region 2 in oocytes and unmethylated in sperm. The 5' region of H19, a paternally imprinted gene, was completely methylated in sperm and unmethylated in oocytes. We examined the methylation status of Snrpn during oocyte growth and maturation. Whereas the DNA of non-growing oocytes was mostly unmethylated, mid-size growing oocytes had a mosaic pattern of allelic methylation, and full acquisition of the methylation imprint was complete by metaphase II. We have identified regions within imprinted genes that show gamete-specific methylation patterns in mature germ cells and demonstrated that maternal methylation imprints on at least one imprinted gene, Snrpn, are established during the postnatal growth phase of oogenesis. Thus, whereas paternal imprints seem to be established early (in diploid gonocytes well before the onset of meiosis), maternal imprints are established late (in growing oocytes that are arrested in the diplotene stage of meiosis). These findings raise the possibility that assisted reproductive technologies that involve in vitro maturation of oocytes may result in developmental abnormalities due to incomplete methylation imprints in immature oocytes.

Animals↗

PubMed2002

Altered methylation patterns in cancer cell genomes: cause or consequence?

CpG islands are associated with at least half of all cellular genes and are normally methylation-free. Dense methylation of cytosine residues within islands causes strong and heritable transcriptional silencing. Such silencing normally occurs almost solely at genes subject to genomic imprinting or to X chromosome inactivation. Aberrant methylation of CpG islands associated with tumor suppressor genes has been proposed to contribute to carcinogenesis. However, questions of mechanisms underlying the cancer changes and the precise consequences for tumorigenesis exist in the field, and must continue to be addressed before the importance of abnormalities in genomic methylation patterns in carcinogenesis can be fully understood. In this article, two workers in DNA methylation, one concentrating on cancer biology and the other on developmental biology, address recurrent questions about cancer epigenetics from different perspectives. The goal is to highlight important controversies in the field which can be productive targets of ongoing and future research.

Animals↗