Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency
Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency
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DOI：
10.1016/j.neurobiolaging.2009.02.013
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发表时间：
2011-02-01
影响因子：
4.2
通讯作者：
Scarpa, Sigfrido
中科院分区：
文献类型：
--
作者：
Fuso, Andrea;Nicolia, Vincenzina;Scarpa, Sigfrido
我们之前已经证明，维生素B缺乏和同型半胱氨酸周期改变的营养模型可能导致淀粉样蛋白沉积增加，这是由于psen1和BACE的过度表达以及随之而来的分泌酶活性增加。我们假设引起同型半胱氨酸周期改变（即高同型半胱氨酸血症）的营养因素可能诱导序列特异性DNA低甲基化和“异常”基因激活。本研究的目的是分析SK-N-BE神经母细胞瘤细胞和TgCRND8小鼠中B族维生素（叶酸、B12和B6）缺乏模式下psen1启动子的甲基化模式。psen1甲基化状态已通过亚硫酸修饰和基因组测序进行评估。我们证明维生素B缺乏会导致5'侧翼区域特定CpG片段的低甲基化；补充s -腺苷蛋氨酸作为甲基供体来逆转这种效应。psen1启动子甲基化状态与基因表达相关。这些发现指出了B族维生素依赖性同型半胱氨酸周期改变与DNA甲基化之间的直接关系，也表明psen1启动子受特定CpG片段甲基化的调节。(C) 2009爱思唯尔公司版权所有。
We have previously shown that a nutritional model of B vitamin deficiency and homocysteine cycle alteration could lead to increased amyloid beta deposition, due to PSEN 1 and BACE over-expression and consequent increase in secretase activity. We hypothesize that nutritional factors causing homocysteine cycle alterations (i.e. hyperhomocysteinemia) could induce sequence-specific DNA hypomethylation and "aberrant" gene activation.Aim of present study was to analyze the methylation pattern of PSEN 1 promoter in SK-N-BE neuroblastoma cells and TgCRND8 mice, in a B vitamin (folate, B12 and B6) deficiency paradigm. PSEN 1 methylation status has been evaluated through bisulphite modification and genomic sequencing. We demonstrate that B vitamin deficiency induces hypomethylation of specific CpG moieties in the 5'-flanking region; S-adenosylmethionine has been supplemented as methyl donor to reverse this effect. PSEN 1 promoter methylation status is correlated with gene expression. These findings pinpoint a direct relationship between B vitamin-dependent alteration of homocysteine cycle and DNA methylation and also indicate that PSEN 1 promoter is regulated by methylation of specific CpG moieties. (C) 2009 Elsevier Inc. All rights reserved.