Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models.
Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models.
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DOI：
10.1186/s13059-015-0827-6
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发表时间：
2015-11-25
期刊：
影响因子：
12.3
通讯作者：
Tycko B
中科院分区：
文献类型：
--
作者：
Mendioroz M;Do C;Jiang X;Liu C;Darbary HK;Lang CF;Lin J;Thomas A;Abu-Amero S;Stanier P;Temkin A;Yale A;Liu MM;Li Y;Salas M;Kerkel K;Capone G;Silverman W;Yu YE;Moore G;Wegiel J;Tycko B
21三体导致唐氏综合症（DS），但额外的染色体导致智力和免疫功能缺陷的机制尚不清楚。在这里，我们分析了CpG甲基化在DS和控制大脑和小脑皮质的成人和胎儿的大脑。我们纯化了神经元和非神经元核和T淋巴细胞，并在这些细胞类型中发现了ds特异性甲基化（DS-DM）的生物学相关基因。一些基因显示脑特异性DS-DM，而另一些基因在T细胞中显示更强的DS-DM。5-甲基胞嘧啶和5-羟基甲基胞嘧啶都与DS-DM有关。成人脑细胞中30%的DS- dm基因在胎儿大脑中也显示DS- dm，表明这些表观遗传变化的早期发生，我们发现DS脑和淋巴细胞的甲基化模式早期成熟。一些，但不是全部，DS-DM基因表现出差异表达。DS-DM优先影响特定转录因子结合位点（TFBSs）内或附近的CpGs，这暗示了TFBS占用改变的机制。对模拟DS的亚染色体复制小鼠模型的脑DNA进行甲基测序，发现与人类DS- dm有部分但显著的重叠，并表明多个21号染色体基因参与下游表观遗传效应。这些数据指出了DS的新的生物学机制，并对染色体复制和非整倍体对表观遗传模式的反效应具有一般意义。本文的在线版本（doi:10.1186/s13059-015-0827-6）包含补充材料，仅供授权用户使用。
Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in each of these cell types. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites (TFBSs), implicating a mechanism involving altered TFBS occupancy. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects. These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning. The online version of this article (doi:10.1186/s13059-015-0827-6) contains supplementary material, which is available to authorized users.