Mother-child transmission of epigenetic information by tunable polymorphic imprinting.
Mother-child transmission of epigenetic information by tunable polymorphic imprinting.
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DOI：
10.1073/pnas.1815005115
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发表时间：
2018-12-18
影响因子：
11.1
通讯作者：
Jones PA
中科院分区：
文献类型：
--
作者：
Carpenter BL;Zhou W;Madaj Z;DeWitt AK;Ross JP;Grønbæk K;Liang G;Clark SJ;Molloy PL;Jones PA
首先，我们的工作提供了在nc 886差异甲基化区域（DMR）的中间DNA甲基化读数的关键生物学解释。nc 886在多个大规模表观基因组关联研究（EWAS）中被鉴定，这些研究没有认识到该区域作为基因组印记施加的连续DMR，这突出了重新检查几个450 k数据集的必要性。其次，严格控制基因组印记被认为是生物体生存力所必需的。多态性印迹的报告仅限于特定的组织类型，如胎盘和大脑。在血液和体细胞组织中，我们发现nc 886印迹在群体中是镶嵌的，并受到母体环境的影响。由DNA甲基化介导的基因组印记将基因表达限制于由亲本来源决定的单个等位基因，并且通常不被认为受到遗传或环境的影响。在这里，我们集中在一个差异甲基化区域（DMR）的约1.9 kb，其中包括一个101 bp的非编码RNA基因（nc 886/VTRNA 2 -1），这是母亲的印记在约75%的人类。这与其他印记基因不同，后者在100%的个体中表现出单等位基因甲基化。DMR在限定DMR边界的着丝粒侧上包括CTCF结合位点，并且在端粒侧上侧接CTCF结合位点。着丝粒CTCF结合位点含有A/C多态性（rs 2346018）; C等位基因与较少的印记相关。婴儿中nc 886 DMR的印迹频率与至少两个非遗传因素有关，即母亲分娩时的年龄和受孕季节。在一个单独的队列中，nc 886印迹与5岁儿童的低体重指数相关。因此，我们提出nc 886 DMR的印记状态是“可调的”，因为它与母体单倍型和产前环境有关。这提供了一个潜在的机制，传递信息，表型的后果，从母亲到孩子。
First, our work provides critical biological interpretation of intermediate DNA methylation readouts at the nc886 differentially methylated region (DMR). nc886 was identified in multiple large-scale epigenome-wide association studies (EWAS) that did not recognize that this region acts as a contiguous DMR imposed by genomic imprinting, highlighting the need to reexamine several 450k data sets. Second, strict control of genomic imprinting was thought to be required for organismal viability. Reports of polymorphic imprinting are limited to specific tissue types such as placenta and brain. In blood and somatic tissues, we show nc886 imprinting is mosaic in the population and influenced by maternal environment. Genomic imprinting mediated by DNA methylation restricts gene expression to a single allele determined by parental origin and is not generally considered to be under genetic or environmental influence. Here, we focused on a differentially methylated region (DMR) of approximately 1.9 kb that includes a 101-bp noncoding RNA gene (nc886/VTRNA2-1), which is maternally imprinted in ∼75% of humans. This is unlike other imprinted genes, which demonstrate monoallelic methylation in 100% of individuals. The DMR includes a CTCF binding site on the centromeric side defining the DMR boundary and is flanked by a CTCF binding site on the telomeric side. The centromeric CTCF binding site contains an A/C polymorphism (rs2346018); the C allele is associated with less imprinting. The frequency of imprinting of the nc886 DMR in infants was linked to at least two nongenetic factors, maternal age at delivery and season of conception. In a separate cohort, nc886 imprinting was associated with lower body mass index in children at 5 y of age. Thus, we propose that the imprinting status of the nc886 DMR is “tunable” in that it is associated with maternal haplotype and prenatal environment. This provides a potential mechanism for transmitting information, with phenotypic consequences, from mother to child.
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影响因子：
7
作者：
Hanna CW;Peñaherrera MS;Saadeh H;Andrews S;McFadden DE;Kelsey G;Robinson WP
通讯作者：
Robinson WP
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Conn, Graeme L.
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影响因子：
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通讯作者：
NIIKAWA, N
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作者：
Bartolomei, Marisa S;Ferguson-Smith, Anne C
通讯作者：
Ferguson-Smith, Anne C