State Key Laboratory of Genetic Engineering, National Demonstration Center for Experimental Biology Education, School of Life Sciences, Fudan University, Shanghai, China.
Department of Chemistry and Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Nucleic Acids Res. 2024 May 8;52(8):4257-4275. doi: 10.1093/nar/gkae093.
Complex biological processes are regulated by both genetic and epigenetic programs. One class of epigenetic modifications is methylation. Evolutionarily conserved methyl-CpG-binding domain (MBD)-containing proteins are known as readers of DNA methylation. MBD5 is linked to multiple human diseases but its mechanism of action remains unclear. Here we report that the zebrafish Mbd5 does not bind to methylated DNA; but rather, it directly binds to 5-methylcytosine (m5C)-modified mRNAs and regulates embryonic development, erythrocyte differentiation, iron metabolism, and behavior. We further show that Mbd5 facilitates removal of the monoubiquitin mark at histone H2A-K119 through an interaction with the Polycomb repressive deubiquitinase (PR-DUB) complex in vivo. The direct target genes of Mbd5 are enriched with both RNA m5C and H2A-K119 ubiquitylation signals. Together, we propose that zebrafish MBD5 is an RNA m5C reader that potentially links RNA methylation to histone modification and in turn transcription regulation in vivo.
复杂的生物过程受到遗传和表观遗传程序的调节。一类表观遗传修饰是甲基化。进化上保守的甲基化-CpG 结合域 (MBD) 含有蛋白质被称为 DNA 甲基化的“读取器”。MBD5 与多种人类疾病有关，但作用机制尚不清楚。在这里，我们报告说，斑马鱼 Mbd5 不会与甲基化 DNA 结合；而是，它直接与 5-甲基胞嘧啶 (m5C) 修饰的 mRNA 结合，并调节胚胎发育、红细胞分化、铁代谢和行为。我们进一步表明，Mbd5 通过与体内多梳抑制去泛素酶 (PR-DUB) 复合物相互作用，促进组蛋白 H2A-K119 上单泛素标记的去除。Mbd5 的直接靶基因富含 RNA m5C 和 H2A-K119 泛素化信号。总之，我们提出斑马鱼 MBD5 是一种 RNA m5C 读取器，它可能将 RNA 甲基化与组蛋白修饰联系起来，并进一步在体内调节转录。
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