Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, Schnittspahnstr. 10, 64287, Darmstadt, Germany.
Section AIDS and newly emerging pathogens, Paul Ehrlich Institute, Paul-Ehrlich-Str. 51-59, 63225, Langen, Germany.
Nat Commun. 2022 Sep 2;13(1):5173. doi: 10.1038/s41467-022-32799-8.
Oxidation of the epigenetic DNA mark 5-methylcytosine by Tet dioxygenases is an established route to diversify the epigenetic information, modulate gene expression and overall cellular (patho-)physiology. Here, we demonstrate that Tet1 and its short isoform Tet1s exhibit distinct nuclear localization during DNA replication resulting in aberrant cytosine modification levels in human and mouse cells. We show that Tet1 is tethered away from heterochromatin via its zinc finger domain, which is missing in Tet1s allowing its targeting to these regions. We find that Tet1s interacts with and is ubiquitinated by CRL4(VprBP). The ubiquitinated Tet1s is then recognized by Uhrf1 and recruited to late replicating heterochromatin. This leads to spreading of 5-methylcytosine oxidation to heterochromatin regions, LINE 1 activation and chromatin decondensation. In summary, we elucidate a dual regulation mechanism of Tet1, contributing to the understanding of how epigenetic information can be diversified by spatio-temporal directed Tet1 catalytic activity.
Tet 双加氧酶氧化表观遗传 DNA 标记 5-甲基胞嘧啶是多样化表观遗传信息、调节基因表达和整体细胞（病理）生理学的既定途径。在这里，我们证明 Tet1 及其短同工型 Tet1s 在 DNA 复制过程中表现出明显的核定位，导致人和小鼠细胞中的异常胞嘧啶修饰水平。我们表明，Tet1 通过其锌指结构域与异染色质隔离，而 Tet1s 中缺失了该结构域，使其能够靶向这些区域。我们发现 Tet1s 与 CRL4(VprBP)相互作用并被其泛素化。然后，泛素化的 Tet1s 被 Uhrf1 识别并募集到复制后期的异染色质。这导致 5-甲基胞嘧啶氧化向异染色质区域扩散、LINE1 激活和染色质去凝聚。总之，我们阐明了 Tet1 的双重调节机制，有助于理解如何通过时空定向 Tet1 催化活性来多样化表观遗传信息。
