Context-dependent functional compensation between Ythdf m(6)A reader proteins.
Context-dependent functional compensation between Ythdf m(6)A reader proteins.
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DOI：
10.1101/gad.340695.120
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发表时间：
2020-10-01
影响因子：
10.5
通讯作者：
Hanna JH
中科院分区：
文献类型：
--
作者：
Lasman L;Krupalnik V;Viukov S;Mor N;Aguilera-Castrejon A;Schneir D;Bayerl J;Mizrahi O;Peles S;Tawil S;Sathe S;Nachshon A;Shani T;Zerbib M;Kilimnik I;Aigner S;Shankar A;Mueller JR;Schwartz S;Stern-Ginossar N;Yeo GW;Geula S;Novershtern N;Hanna JH
在这里，Lasman等人试图理解三种同源m6 A结合蛋白（Ythdf 1、Ythdf 2和Ythdf 3）的作用，并系统地敲除Mettl 3写入器、每个Ythdf读取器和三个读取器（三重KO）。他们的发现为Ythdf阅读器功能提出了一种新的模型，当所有三种阅读器在相同的细胞类型中等价共表达时，存在深刻的剂量依赖性冗余。N6-甲基腺苷（m6 A）修饰是最普遍的转录后mRNA修饰，调节mRNA的衰变和剪接。它在正常发育、分化和疾病进展过程中发挥重要作用。这种修饰是由一组写入器、擦除器和读取器蛋白调节的。YTH结构域蛋白家族由三种同源的m6 A结合蛋白Ythdf 1、Ythdf 2和Ythdf 3组成，它们被认为具有不同的细胞功能。然而，它们的序列相似性和它们结合相同靶标的倾向表明它们可能具有重叠的作用。我们系统地淘汰（KO）Mettl 3编写器，每个Ythdf读取器，以及三个读取器（三重KO）。然后，我们估计在小鼠配子发生，出生后的活力，并在体外小鼠胚胎干细胞（mESC）的影响。在配子发生中，随着缺失在过程中发生得更早，Mettl 3-KO的严重程度会增加，并且Ythdf 2具有主导作用，无法由Ythdf 1或Ythdf 3补偿，因为不同细胞类型中读者的表达模式存在差异，无论是在数量上还是在空间位置上。敲除这三个读码器并系统地测试可行的后代基因型，揭示了读码器在早期发育过程中的作用冗余，这是Ythdf 1/2/3基因剂量依赖性的。最后，在mESC中，在三种Ythdf阅读器蛋白之间存在补偿，因为对分化的抗性和对mRNA衰减的显著影响仅发生在三重KO细胞中，而不发生在单个科斯中。因此，我们提出了一个新的模型的Ythdf读者功能，其中有深刻的剂量依赖性冗余时，所有三个读者等价共表达在相同的细胞类型。
Here, Lasman et al. sought to understand the role of three homologous m6A-binding proteins (Ythdf1, Ythdf2, and Ythdf3) and systematically knocked out the Mettl3 writer, each of the Ythdf readers, and the three readers together (triple-KO). Their findings suggest a novel model for the Ythdf reader function, in which there is profound dosage-dependent redundancy when all three readers are equivalently coexpressed in the same cell types. The N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader proteins. The YTH domain family of proteins consists of three homologous m6A-binding proteins, Ythdf1, Ythdf2, and Ythdf3, which were suggested to have different cellular functions. However, their sequence similarity and their tendency to bind the same targets suggest that they may have overlapping roles. We systematically knocked out (KO) the Mettl3 writer, each of the Ythdf readers, and the three readers together (triple-KO). We then estimated the effect in vivo in mouse gametogenesis, postnatal viability, and in vitro in mouse embryonic stem cells (mESCs). In gametogenesis, Mettl3-KO severity is increased as the deletion occurs earlier in the process, and Ythdf2 has a dominant role that cannot be compensated by Ythdf1 or Ythdf3, due to differences in readers’ expression pattern across different cell types, both in quantity and in spatial location. Knocking out the three readers together and systematically testing viable offspring genotypes revealed a redundancy in the readers’ role during early development that is Ythdf1/2/3 gene dosage-dependent. Finally, in mESCs there is compensation between the three Ythdf reader proteins, since the resistance to differentiate and the significant effect on mRNA decay occur only in the triple-KO cells and not in the single KOs. Thus, we suggest a new model for the Ythdf readers function, in which there is profound dosage-dependent redundancy when all three readers are equivalently coexpressed in the same cell types.
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影响因子：
2.5
作者：
Lasman L;Hanna JH;Novershtern N
通讯作者：
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影响因子：
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影响因子：
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作者：
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影响因子：
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