Reactivation of imprinted genes in Prader-Willi syndrome.

普瑞德威利综合征中印记基因的重新激活。

• 批准号: 12670719
• 负责人: SAITOH Shinji
• 金额: $ 2.37万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670719/
• 关键词: imprinting; epigenetics; DNA methylation; histone acetylation; Prader-Willi syndrome; Angelman syndrome; Prader-Willi症候群; ゲノム刷り込み現象; DNAメチル化; ヒストンアセチル化; Proder-Willi症候群

Prader-Willi syndrome (PWS) is associated with silencing of several imprinted genes located in 15q11-q13. These genes are epigenetically silenced through genomic imprinting although the genes are present. We have demonstrated that SNURF-SNRPN, which is a key imprinted locus in 15q11-q13, could be reactivated by drug treatment using 5-azadeoxycytidine (5-aza-dC) that inhibits DNA methylation. This reactivation was associated with not only demetylation of the CpG island of SNURF-SNRPN, but also increased level of histone acetylation. These results indicated that DNA methylation and histone acetylation played the critical roles in silencing of the imprinted genes.We further investigated the possible reactivation of the homologous imprinted genes in mice. We used the fibroblasts established from the PWS mice models as well as control mice. Reactivation of Snurf-Snrpn in mice by 5-azadC was not as strong as in human. These preliminary results will help further investigation using mice models to test potential pharmaceutical treatment of imprinting related-disorders.

Prader-Willi综合征(PWS)与位于15q11-q13的几个印记基因的沉默有关。这些基因通过基因组印记在表观遗传上沉默，尽管这些基因是存在的。我们已经证明，SNURF-Snrpn是15q11-q13中的一个关键印迹基因，可以通过5-氮杂脱氧胞苷(5-azadeoxcytidine，5-aza-DC)抑制DNA甲基化而重新激活。这种重新激活不仅与SNURF-Snrpn的CpG岛去甲基化有关，而且与组蛋白乙酰化水平的增加有关。这些结果表明DNA甲基化和组蛋白乙酰化在印迹基因沉默中起着关键作用。我们进一步研究了同源印迹基因在小鼠体内重新激活的可能性。我们使用从PWS小鼠模型和对照小鼠建立的成纤维细胞。5-azadC对小鼠sNurf-Snrpn的再激活作用不如人强。这些初步结果将有助于进一步的研究，使用小鼠模型来测试印记相关疾病的潜在药物治疗。

项目成果

Saitoh S, Wada T: "Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader-Willi syndrome"Am J Hum Genet. 66. 1958-1962 (2000)

Saitoh S、Wada T：“Prader-Willi 综合征中关键印记基因位点的亲本特异性组蛋白乙酰化和重新激活”Am J Hum Genet。

Saitoh S, Wada T.: "Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader-Willi syndrome"Am J Hum Genet. 66. 1958-1962 (2000)

Saitoh S、Wada T.：“Prader-Willi 综合征中关键印记基因位点的亲本特异性组蛋白乙酰化和重新激活”Am J Hum Genet。

Saitoh S: "Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader-Willi syndrome."Am J Hum Genet. 66. 1958-1962 (2000)

Saitoh S：“Prader-Willi 综合征中关键印记基因位点的亲本特异性组蛋白乙酰化和重新激活。”Am J Hum Genet。

Saitoh S, et al.: "Oculocutaneous albinism type 2 with P gene missense mutation in a patient with Angelman syndrome"J Med Genet. 37. 392-394 (2000)

Saitoh S 等人：“Angelman 综合征患者伴有 P 基因错义突变的 2 型眼皮肤白化病”J Med Genet。

斉藤伸治: "Prader-Willi症候群"小児科診療. 64. 54-54 (2001)

Shinji Saito：“Prader-Willi 综合征”儿科实践。64. 54-54 (2001)。