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人源DNMT3A的过表达诱导大鼠精子中活性DNA甲基化变化的代际遗传。

Overexpression of Human-Derived DNMT3A Induced Intergenerational Inheritance of Active DNA Methylation Changes in Rat Sperm.

作者信息

Zheng Xiaoguo, Li Zhenhua, Wang Guishuan, Li Zhengzheng, Liang Ajuan, Wang Hanshu, Dai Yubing, Huang Xingxu, Chen Xuejin, Ma Yuanwu, Sun Fei

机构信息

International Peace Maternity & Child Health Hospital, Institute of Embryo-Fetal Original Adult Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Center for Reproductive Medicine, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.

出版信息

Front Genet. 2017 Dec 12;8:207. doi: 10.3389/fgene.2017.00207. eCollection 2017.

DOI:10.3389/fgene.2017.00207
PMID:29312436
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5733082/
Abstract

DNA methylation is the major focus of studies on paternal epigenetic inheritance in mammals, but most previous studies about inheritable DNA methylation changes are passively induced by environmental factors. However, it is unclear whether the active changes mediated by variations in DNA methyltransferase activity are heritable. Here, we established human-derived ( transgenic rats to study the effect of overexpression on the DNA methylation pattern of rat sperm and to investigate whether this actively altered DNA methylation status is inheritable. Our results revealed that was overexpressed in the testis of transgenic rats and induced genome-wide alterations in the DNA methylation pattern of rat sperm. Among 5438 reliable loci identified with 64 primer-pair combinations using a methylation-sensitive amplification polymorphism method, 28.01% showed altered amplified band types. Among these amplicons altered loci, 68.42% showed an altered DNA methylation status in the offspring of transgenic rats compared with wild-type rats. Further analysis based on loci which had identical DNA methylation status in all three biological replicates revealed that overexpression of in paternal testis induced hypermethylation in sperm of both genotype-negative and genotype-positive offspring. Among the differentially methylated loci, 34.26% occurred in both positive and negative offspring of transgenic rats, indicating intergenerational inheritance of active DNA methylation changes in the absence of transmission. Furthermore, 75.07% of the inheritable loci were hyper-methylated while the remaining were hypomethylated. Distribution analysis revealed that the DNA methylation variations mainly occurred in introns and intergenic regions. Functional analysis revealed that genes related to differentially methylated loci were involved in a wide range of functions. Finally, this study demonstrated that active DNA methylation changes induced by expression were intergenerationally inherited by offspring without transmission of the transgene, which provided evidence for the transmission of active endogenous-factors-induced epigenetic variations.

摘要

DNA甲基化是哺乳动物父系表观遗传研究的主要焦点，但此前大多数关于可遗传DNA甲基化变化的研究都是由环境因素被动诱导的。然而，尚不清楚由DNA甲基转移酶活性变化介导的主动变化是否可遗传。在此，我们建立了人源转基因大鼠，以研究[具体基因]过表达对大鼠精子DNA甲基化模式的影响，并调查这种主动改变的DNA甲基化状态是否可遗传。我们的结果显示，[具体基因]在转基因大鼠的睾丸中过表达，并诱导大鼠精子DNA甲基化模式发生全基因组改变。使用甲基化敏感扩增多态性方法，通过64对引物组合鉴定出5438个可靠位点，其中28.01%显示扩增条带类型改变。在这些扩增条带改变的位点中，与野生型大鼠相比，68.42%在转基因大鼠后代中显示出DNA甲基化状态改变。基于在所有三个生物学重复中具有相同DNA甲基化状态的位点进行的进一步分析表明，父系睾丸中[具体基因]的过表达在基因型阴性和基因型阳性后代的精子中均诱导了高甲基化。在差异甲基化位点中，34.26%出现在转基因大鼠的阳性和阴性后代中，表明在没有[具体基因]传递的情况下，主动DNA甲基化变化的代际遗传。此外，75.07%的可遗传位点是高甲基化的，其余是低甲基化的。分布分析表明，DNA甲基化变异主要发生在内含子和基因间区域。功能分析表明，与差异甲基化位点相关的基因涉及广泛的功能。最后，本研究表明，由[具体基因]表达诱导的主动DNA甲基化变化可被后代代际遗传，而无需转基因的传递，这为内源性因素诱导的表观遗传变异的传递提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/159f462a63a9/fgene-08-00207-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/336531e03bf4/fgene-08-00207-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/4397f751fc4a/fgene-08-00207-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/1fe791ecf253/fgene-08-00207-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/97e43054b8a0/fgene-08-00207-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/08957b1a8a8a/fgene-08-00207-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/159f462a63a9/fgene-08-00207-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/336531e03bf4/fgene-08-00207-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/4397f751fc4a/fgene-08-00207-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/1fe791ecf253/fgene-08-00207-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/97e43054b8a0/fgene-08-00207-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/08957b1a8a8a/fgene-08-00207-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8573/5733082/159f462a63a9/fgene-08-00207-g0006.jpg

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