Harbin Institute of Technology, 150001 Heilongjiang, China.
Department of Biology, Southern University of Science and Technology of China, 518055 Guangdong, China.
Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3603-3609. doi: 10.1073/pnas.1910862117. Epub 2020 Feb 3.
5-Methylcytosine (mC) is a RNA modification that exists in tRNAs and rRNAs and was recently found in mRNAs. Although it has been suggested to regulate diverse biological functions, whether mC RNA modification influences adult stem cell development remains undetermined. In this study, we show that Ypsilon schachtel (YPS), a homolog of human Y box binding protein 1 (YBX1), promotes germ line stem cell (GSC) maintenance, proliferation, and differentiation in the ovary by preferentially binding to mC-containing RNAs. YPS is genetically demonstrated to function intrinsically for GSC maintenance, proliferation, and progeny differentiation in the ovary, and human YBX1 can functionally replace YPS to support normal GSC development. Highly conserved cold-shock domains (CSDs) of YPS and YBX1 preferentially bind to mC RNA in vitro. Moreover, YPS also preferentially binds to mC-containing RNAs, including mRNAs, in germ cells. The crystal structure of the YBX1 CSD-RNA complex reveals that both hydrophobic stacking and hydrogen bonds are critical for mC binding. Overexpression of RNA-binding-defective YPS and YBX1 proteins disrupts GSC development. Taken together, our findings show that mC RNA modification plays an important role in adult stem cell development.
5- 甲基胞嘧啶（mC）是一种存在于 tRNA 和 rRNA 中的 RNA 修饰物，最近在 mRNA 中也发现了它。尽管有人提出它可以调节多种生物功能，但 mC RNA 修饰是否影响成年干细胞的发育仍未确定。在这项研究中，我们发现 Ypsilon schachtel（YPS），一种与人 Y 盒结合蛋白 1（YBX1）的同源物，通过优先结合含有 mC 的 RNA 来促进生殖干细胞（GSC）在卵巢中的维持、增殖和分化。遗传证据表明，YPS 内在地作用于 GSC 在卵巢中的维持、增殖和后代分化，而人 YBX1 可以替代 YPS 发挥功能以支持正常的 GSC 发育。YPS 和 YBX1 的高度保守的冷休克结构域（CSD）优先在体外结合 mC RNA。此外，YPS 还优先结合包括 mRNAs 在内的含有 mC 的 RNA 在生殖细胞中。YBX1 CSD-RNA 复合物的晶体结构表明，疏水性堆积和氢键对于 mC 结合都很重要。过表达 RNA 结合缺陷的 YPS 和 YBX1 蛋白会破坏 GSC 的发育。总之，我们的研究结果表明，mC RNA 修饰在成年干细胞发育中起着重要作用。
