Profiling of m6A RNA modifications identified an age-associated regulation of AGO2 mRNA stability.
Profiling of m6A RNA modifications identified an age-associated regulation of AGO2 mRNA stability.
复制标题
DOI：
10.1111/acel.12753
复制
发表时间：
2018-06
期刊：
影响因子：
7.8
通讯作者：
Yoon JH
中科院分区：
文献类型：
--
作者：
Min KW;Zealy RW;Davila S;Fomin M;Cummings JC;Makowsky D;Mcdowell CH;Thigpen H;Hafner M;Kwon SH;Georgescu C;Wren JD;Yoon JH
基因表达在多种哺乳动物生理学中受到动态调节。在哺乳动物衰老过程中，蛋白质表达发生变化，这些变化受到转录、转录后和翻译后调节步骤的高度控制。虽然在衰老过程中有人类转录本的全球概况，但转录本在年轻和老年群体之间差异表达的机制仍不清楚。在这里，我们报告了来自年轻和老年队列的人外周血单核细胞（PBMC）的N6-甲基腺苷（m6 A）RNA修饰谱。一个m6 A的RNA图谱确定了在衰老过程中整体RNA甲基化的减少，以及蛋白质编码mRNA的主要修饰。m6 A修饰的转录物往往比未修饰的转录物表达更高。在许多甲基化的mRNA中，DROSHA和AGO 2的mRNA在年轻PBMC中高度甲基化，这与老年PBMC队列中AGO 2 mRNA的稳态水平降低一致。同样，AGO 2在增殖的人二倍体成纤维细胞（HDF）中的下调也与AGO 2 mRNA修饰和稳态水平的降低相关。此外，在HDFs中，RNA甲基转移酶的过表达稳定AGO 2 mRNA，但不稳定DROSHA和DICER 1 mRNA。此外，年轻和老年PBMC中miRNA的丰度也发生了变化，这可能是由于与AGO 2表达相关，如在AGO 2耗尽的HDF中观察到的。综上所述，我们揭示了mRNA甲基化对AGO 2 mRNA丰度的作用，从而导致人类衰老过程中miRNA表达的抑制。
Gene expression is dynamically regulated in a variety of mammalian physiologies. During mammalian aging, there are changes that occur in protein expression that are highly controlled by the regulatory steps in transcription, post‐transcription, and post‐translation. Although there are global profiles of human transcripts during the aging processes available, the mechanism(s) by which transcripts are differentially expressed between young and old cohorts remains unclear. Here, we report on N6‐methyladenosine (m6A) RNA modification profiles of human peripheral blood mononuclear cells (PBMCs) from young and old cohorts. An m6A RNA profile identified a decrease in overall RNA methylation during the aging process as well as the predominant modification on proteincoding mRNAs. The m6A‐modified transcripts tend to be more highly expressed than nonmodified ones. Among the many methylated mRNAs, those of DROSHA and AGO2 were heavily methylated in young PBMCs which coincided with a decreased steady‐state level of AGO2 mRNA in the old PBMC cohort. Similarly, downregulation of AGO2 in proliferating human diploid fibroblasts (HDFs) also correlated with a decrease in AGO2 mRNA modifications and steady‐state levels. In addition, the overexpression of RNA methyltransferases stabilized AGO2 mRNA but not DROSHA and DICER1 mRNA in HDFs. Moreover, the abundance of miRNAs also changed in the young and old PBMCs which are possibly due to a correlation with AGO2 expression as observed in AGO2‐depleted HDFs. Taken together, we uncovered the role of mRNA methylation on the abundance of AGO2 mRNA resulting in the repression of miRNA expression during the process of human aging.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
人外周血中与年龄相关的 microRNA 表达与全因死亡率和年龄相关特征相关。
影响因子：
7.8
作者：
Huan T;Chen G;Liu C;Bhattacharya A;Rong J;Chen BH;Seshadri S;Tanriverdi K;Freedman JE;Larson MG;Murabito JM;Levy D
通讯作者：
Levy D
影响因子：
16
作者：
Wang X;He C
通讯作者：
He C
影响因子：
16
作者：
Mukherjee N;Corcoran DL;Nusbaum JD;Reid DW;Georgiev S;Hafner M;Ascano M Jr;Tuschl T;Ohler U;Keene JD
通讯作者：
Keene JD