Ichino Lucia, Boone Brandon A, Strauskulage Luke, Harris C Jake, Kaur Gundeep, Gladstone Matthew A, Tan Maverick, Feng Suhua, Jami-Alahmadi Yasaman, Duttke Sascha H, Wohlschlegel James A, Cheng Xiaodong, Redding Sy, Jacobsen Steven E
Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
Science. 2021 Jun 3. doi: 10.1126/science.abg6130.
DNA methylation is associated with transcriptional repression of eukaryotic genes and transposons, but the downstream mechanism of gene silencing is largely unknown. Here we describe two methyl-CpG binding domain proteins, MBD5 and MBD6, that are recruited to chromatin by recognition of CG methylation, and redundantly repress a subset of genes and transposons without affecting DNA methylation levels. These methyl-readers recruit a J-domain protein, SILENZIO, that acts as a transcriptional repressor in loss-of-function and gain-of-function experiments. J-domain proteins often serve as co-chaperones with HSP70s. Indeed, we found that SILENZIO's conserved J-domain motif was required for its interaction with HSP70s and for its silencing function. These results uncover an unprecedented role of a molecular chaperone J-domain protein in gene silencing downstream of DNA methylation.
DNA甲基化与真核基因和转座子的转录抑制相关，但基因沉默的下游机制在很大程度上尚不清楚。在这里，我们描述了两种甲基-CpG结合域蛋白，MBD5和MBD6，它们通过识别CG甲基化被招募到染色质上，并在不影响DNA甲基化水平的情况下冗余抑制一部分基因和转座子。这些甲基阅读蛋白招募了一种J结构域蛋白SILENZIO，在功能丧失和功能获得实验中，它作为一种转录抑制因子发挥作用。J结构域蛋白通常作为HSP70s的共伴侣发挥作用。事实上，我们发现SILENZIO保守的J结构域基序是其与HSP70s相互作用及其沉默功能所必需的。这些结果揭示了分子伴侣J结构域蛋白在DNA甲基化下游基因沉默中前所未有的作用。
