The link between DNA methylation and neurodevelopmental disorders is well established. However, how DNA methylation is fine-tuned—ensuring precise gene expression and developmental fidelity—remains poorly understood. PROSER1, a known TET2 interactor, was recently linked to a severe neurodevelopmental disorder. Here, we demonstrate that PROSER1 interacts with all TET enzymes and stabilizes chromatin-bound TET–OGT–PROSER1–DBHS (TOPD) complexes, which regulate DNA demethylation and developmental gene expression. Surprisingly, we found that PROSER1 also sequesters TET enzymes, preventing widespread demethylation and transposable element derepression. Our findings identify PROSER1 as a key factor that both positively and negatively regulates DNA demethylation essential for mammalian neurodevelopment.

中文翻译：

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PROSER1 通过双重机制调节 DNA 去甲基化，以防止综合征性发育畸形


DNA 甲基化与神经发育障碍之间的联系已得到充分证实。然而，如何微调 DNA 甲基化——确保精确的基因表达和发育保真度——仍然知之甚少。PROSER1 是一种已知的 TET2 相互作用器，最近与一种严重的神经发育障碍有关。在这里，我们证明 PROSER1 与所有 TET 酶相互作用并稳定染色质结合的 TET-OGT-PROSER1-DBHS （TOPD） 复合物，这些复合物调节 DNA 去甲基化和发育基因表达。令人惊讶的是，我们发现 PROSER1 还可以隔离 TET 酶，防止广泛的去甲基化和转座因子去抑制。我们的研究结果表明，PROSER1 是正向和负向调节哺乳动物神经发育所必需的 DNA 去甲基化的关键因素。