N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer's disease.
N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer's disease.
复制标题
DOI：
10.1186/s13059-020-02249-z
复制
发表时间：
2021-01-05
期刊：
影响因子：
12.3
通讯作者：
Jin P
中科院分区：
文献类型：
--
作者：
Shafik AM;Zhang F;Guo Z;Dai Q;Pajdzik K;Li Y;Kang Y;Yao B;Wu H;He C;Allen EG;Duan R;Jin P
已知N6-甲基腺苷（m6 A）修饰影响RNA代谢的许多方面，包括mRNA稳定性和翻译，并且在大脑中非常普遍。我们发现，m6 A修饰显示在神经发育和衰老的时间和空间动态。时间差异甲基化的基因更容易发生mRNA表达变化，并影响与神经系统发育相关的许多途径。此外，m6 A显示出独特的组织特异性甲基化谱，这在下丘脑中最明显。组织特异性甲基化与mRNA表达的增加相关，并与组织特异性发育过程相关。在衰老过程中，我们观察到随着年龄的增加，在小鼠和人类中的m6 A位点显著增加。我们显示小鼠和人类之间的高度重叠;然而，与小鼠相比，年轻和老年的人类始终显示出更多的m6 A位点。发现差异m6 A位点富集在影响衰老相关途径的基因的替代非翻译区中。这些m6 A位点与对mRNA表达的强烈负面影响相关。我们还表明，许多阿尔茨海默病相关的转录表现出降低m6 A甲基化在阿尔茨海默病的小鼠模型，这是与蛋白质水平降低。我们的研究结果表明，m6 A发挥了重要的功能，在早期和晚期的大脑发育的时空方式。此外，m6 A控制参与阿尔茨海默病相关途径的关键基因的蛋白质水平，这表明m6 A在衰老和神经退行性疾病中起着重要作用。
N6-methyladenosine (m6A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain. We show that m6A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m6A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m6A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m6A sites compared to mice. Differential m6A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m6A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m6A methylation in a mouse model of Alzheimer’s disease, which is correlated with reduced protein levels. Our results suggest that m6A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m6A controls protein levels of key genes involved in Alzheimer’s disease-associated pathways, suggesting that m6A plays an important role in aging and neurodegenerative disease.
登录
查看更多内容
影响因子：
--
作者：
Kaklamani V;Yi N;Sadim M;Siziopikou K;Zhang K;Xu Y;Tofilon S;Agarwal S;Pasche B;Mantzoros C
通讯作者：
Mantzoros C
DOI：
10.1261/rna.058206.116
发表时间：
2017-10
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Antanaviciute A;Baquero-Perez B;Watson CM;Harrison SM;Lascelles C;Crinnion L;Markham AF;Bonthron DT;Whitehouse A;Carr IM
通讯作者：
Carr IM
YTHDF2 通过直接招募 CCR4-NOT 去腺苷酶复合物来破坏含有 m(6)A 的 RNA 的稳定性。
影响因子：
16.6
作者：
Du, Hao;Zhao, Ya;He, Jinqiu;Zhang, Yao;Xi, Hairui;Liu, Mofang;Ma, Jinbiao;Wu, Ligang
通讯作者：
Wu, Ligang
影响因子：
64.8
作者：
Lence, Tina;Akhtar, Junaid;Roignant, Jean-Yves
通讯作者：
Roignant, Jean-Yves
影响因子：
10.5
作者：
Ke S;Alemu EA;Mertens C;Gantman EC;Fak JJ;Mele A;Haripal B;Zucker-Scharff I;Moore MJ;Park CY;Vågbø CB;Kusśnierczyk A;Klungland A;Darnell JE Jr;Darnell RB
通讯作者：
Darnell RB