Department of Urology, Biochemistry, and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
PLoS Genet. 2011 Feb 3;7(2):e1001286. doi: 10.1371/journal.pgen.1001286.
How epigenetic information is propagated during somatic cell divisions is still unclear but is absolutely critical for preserving gene expression patterns and cellular identity. Here we show an unanticipated mechanism for inheritance of DNA methylation patterns where the epigenetic mark not only recruits the catalyzing enzyme but also regulates the protein level, i.e. the enzymatic product (5-methylcytosine) determines the level of the methylase, thus forming a novel homeostatic inheritance system. Nucleosomes containing methylated DNA stabilize de novo DNA methyltransferases, DNMT3A/3B, allowing little free DNMT3A/3B enzymes to exist in the nucleus. Stabilization of DNMT3A/3B on nucleosomes in methylated regions further promotes propagation of DNA methylation. However, reduction of cellular DNA methylation levels creating more potential CpG substrates counter-intuitively results in a dramatic decrease of DNMT3A/3B proteins due to diminished nucleosome binding and subsequent degradation of the unstable free proteins. These data show an unexpected self-regulatory inheritance mechanism that not only ensures somatic propagation of methylated states by DNMT1 and DNMT3A/3B enzymes but also prevents aberrant de novo methylation by causing degradation of free DNMT3A/3B enzymes.
DNA 甲基化模式如何在体细胞分裂过程中传递尚不清楚，但对于维持基因表达模式和细胞身份绝对至关重要。在这里，我们展示了一种意想不到的 DNA 甲基化模式遗传的机制，其中表观遗传标记不仅募集催化酶，而且还调节蛋白质水平，即酶产物（5-甲基胞嘧啶）决定甲基转移酶的水平，从而形成一种新的平衡遗传系统。含有甲基化 DNA 的核小体稳定从头 DNA 甲基转移酶（DNMT3A/3B），使得核内几乎不存在游离的 DNMT3A/3B 酶。DNMT3A/3B 在甲基化区域的核小体上的稳定进一步促进了 DNA 甲基化的传播。然而，细胞内 DNA 甲基化水平的降低创造了更多潜在的 CpG 底物，这反直觉地导致 DNMT3A/3B 蛋白急剧减少，这是由于核小体结合减少和随后不稳定的游离蛋白降解所致。这些数据显示了一种意想不到的自我调节遗传机制，该机制不仅通过 DNMT1 和 DNMT3A/3B 酶确保甲基化状态的体细胞传递，而且通过导致游离 DNMT3A/3B 酶的降解来防止异常的从头甲基化。
