Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker.
Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker.
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DOI：
10.1038/s41467-021-24036-5
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发表时间：
2021-06-17
影响因子：
16.6
通讯作者：
Watson ED
中科院分区：
文献类型：
--
作者：
Blake GET;Zhao X;Yung HW;Burton GJ;Ferguson-Smith AC;Hamilton RS;Watson ED
跨代表观遗传背后的机制尚不清楚，特别是通过母系祖父母系。我们以前的研究表明，Mtrr亚型突变导致小鼠叶酸代谢中断，导致先天性畸形的跨代表观遗传。任何一个外祖父母都可以引发这种现象，这种现象持续至少四代野生型。在这里，我们使用全基因组的方法来揭示Mtrr模型的遗传稳定性和Mtrr突变的外祖父种系的全基因组差异DNA甲基化。我们观察到，当表观遗传重编程发生时，野生型孙子和曾孙表现出与种系甲基化缺陷相关的转录变化。一个区域包括Hira基因，其在胚胎中以将Hira转录物表达区分为母体表型遗传的生物标志物的方式错误表达至少三个野生型世代。小鼠叶酸代谢异常导致先天性畸形的跨代表观遗传。在这里，作者提供了叶酸代谢缺陷导致生殖系表观遗传不稳定性的证据，并观察到胚胎中Hira的多代错误表达，暗示Hira转录水平是母体表型遗传的生物标志物。
The mechanism behind transgenerational epigenetic inheritance is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrr hypomorphic mutation results in transgenerational epigenetic inheritance of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. Here, we use genome-wide approaches to reveal genetic stability in the Mtrr model and genome-wide differential DNA methylation in the germline of Mtrr mutant maternal grandfathers. We observe that, while epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional changes that correlate with germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos for at least three wildtype generations in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance. Abnormal folate metabolism in mice results in transgenerational epigenetic inheritance of congenital malformations. Here, the authors provide evidence that defective folate metabolism causes germline epigenetic instability and observe multigenerational misexpression of Hira in embryos, implicating Hira transcript levels as a biomarker of maternal phenotypic inheritance.
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DOI：
10.1126/science.1229277
发表时间：
2013-01-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hackett JA;Sengupta R;Zylicz JJ;Murakami K;Lee C;Down TA;Surani MA
通讯作者：
Surani MA
影响因子：
11.8
作者：
Branco MR;King M;Perez-Garcia V;Bogutz AB;Caley M;Fineberg E;Lefebvre L;Cook SJ;Dean W;Hemberger M;Reik W
通讯作者：
Reik W
影响因子：
25
作者：
Gapp, Katharina;Jawaid, Ali;Sarkies, Peter;Bohacek, Johannes;Pelczar, Pawel;Prados, Julien;Farinelli, Laurent;Miska, Eric;Mansuy, Isabelle M.
通讯作者：
Mansuy, Isabelle M.
影响因子：
3.9
作者：
Brunner AM;Nanni P;Mansuy IM
通讯作者：
Mansuy IM
DOI：
10.1126/science.aaf7040
发表时间：
2016-07-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Holland ML;Lowe R;Caton PW;Gemma C;Carbajosa G;Danson AF;Carpenter AA;Loche E;Ozanne SE;Rakyan VK
通讯作者：
Rakyan VK