Table_1_Transient DNMT3L Expression Reinforces Chromatin Surveillance to Halt Senescence Progression in Mouse Embryonic Fibroblast.pdf

Global heterochromatin reduction, which is one of the hallmarks of senescent cells, is associated with reduced transposable element repression and increased risk of chromatin instability. To ensure genomic integrity, the irreparable cells in a population exit permanently from the cell cycle, and this process is termed “senescence.” However, senescence only blocks the expansion of unwanted cells, and the aberrant chromatin of senescent cells remains unstable. Serendipitously, we found that the transient ectopic expression of a repressive epigenetic modulator, DNA methyltransferase 3-like (DNMT3L) was sufficient to delay the premature senescence progression of late-passage mouse embryonic fibroblasts (MEFs) associated with a tightened global chromatin structure. DNMT3L induces more repressive H3K9 methylation on endogenous retroviruses and downregulates the derepressed transposons in aging MEFs. In addition, we found that a pulse of ectopic DNMT3L resulted in the reestablishment of H3K27me3 on polycomb repressive complex 2 (PRC2)-target genes that were derepressed in old MEFs. We demonstrated that ectopic DNMT3L interacted with PRC2 in MEFs. Our data also suggested that ectopic DNMT3L might guide PRC2 to redress deregulated chromatin regions in cells undergoing senescence. This study might lead to an epigenetic reinforcement strategy for overcoming aging-associated epimutation and senescence.

全局异染色质丢失是衰老细胞的标志性特征之一，其与转座因子抑制作用减弱以及染色质不稳定风险升高密切相关。为维持基因组完整性，细胞群体中无法修复的细胞会永久退出细胞周期，这一过程被称为“细胞衰老”。然而，细胞衰老仅能阻滞异常细胞的扩增，衰老细胞的异常染色质仍处于不稳定状态。机缘巧合之下，我们发现抑制性表观遗传调控因子DNA甲基转移酶3样蛋白（DNA methyltransferase 3-like, DNMT3L）的瞬时异位表达，足以延缓传代晚期小鼠胚胎成纤维细胞（mouse embryonic fibroblasts, MEFs）的早衰进程，且该过程伴随全局染色质结构的紧致化。DNMT3L可在内源性逆转录病毒上诱导更多具有抑制活性的H3K9甲基化修饰，并下调衰老MEFs中去抑制的转座子。此外，我们发现脉冲式异位表达DNMT3L，可使老年MEFs中被去抑制的多梳抑制复合体2（polycomb repressive complex 2, PRC2）靶基因重新建立H3K27me3修饰。我们证实，在MEFs中异位表达的DNMT3L可与PRC2发生相互作用。我们的数据还表明，异位表达的DNMT3L可能会引导PRC2，以矫正衰老细胞中调控失调的染色质区域。本研究或可催生一种表观遗传强化策略，用于对抗衰老相关的表观突变与细胞衰老。