2002 Fiscal Year Final Research Report Summary
Genomic imprinting on the development of the human trophoblastic
| Project/Area Number |
13671725
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | Kyushu University |
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Principal Investigator |
ARIMA Takahiro Medical Institute of Bioregulation Kyushu Univ. Research Associate, 生体防御医学研究所, 助手 (80253532)
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| Co-Investigator(Kenkyū-buntansha) |
WAKE Norio Medical Institute of Bioregulation Kyushu Univ. Professor, 生体防御医学研究所, 教授 (50158606)
MATSUDA Takao Medical Institute of Bioregulation Kyushu Univ. Research Associate, 生体防御医学研究所, 助手 (10304825)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Genome imprint / HYMAI / ZAC / DNA methylation / TNDM / parthenogenetic embryo / placenta / Complete mole / Imprint control region |
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| Research Abstract |
Transient neonatal diabetes mellitus (TNDM) is associated with intrauterine growth retardation, dehydration and a lack of insulin. Some TNDM patients exhibit paternal uniparental disomy (UPD) of chromosome 6q24, where at least two imprinted genes, HYMAI and ZAC, have so far been characterised. Here we show that the differentially methylated CpG island that partially overlaps mZac1 and mHymai at the syntenic mouse locus is the likely imprinting control region (ICR) for the approximately 120-200 kb domain. The region is unmethylated in sperm and methylated in oocytes, a difference that persists between parental alleles throughout pre- and postimplantation development. We also show that within this ICR, there is a region that exhibits a high degree of homology between mouse and human. Using a reporter expression assay, we demonstrate that this conserved region acts as a strong transcriptional repressor when methylated. Finally, we provide in vivo evidence that in the majority of TNDM patients with a normal karyotype, there is a loss of methylation within the highly homologous region. We propose that this ICR regulates expression of imprinted genes within the domain; epigenetic or genetic mutations of this region probably result in TNDM, possibly by affecting expression of ZAC in the pancreas and/or the pituitary. Aberrant epigenetic changes in the region associated with a loss of function of ZAC may also contribute to cancers.
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