小柯机器人

瑞士巴塞尔大学Dirk Schübeler研究团队的最新研究表明直接抑制转录因子（TF）结合是DNA甲基化抑制基因表达和重复的主要形式。2022年12月5日出版的《自然-遗传学》杂志发表了这项成果。

研究人员发现，小鼠胚胎干细胞、衍生神经元或人类细胞系中缺失具有功能性甲基-CpG结合域（MBD）的所有四种蛋白质组合，不会重新激活基因或重复甲基化启动子。然而，如果去除DNA甲基化，则会激活被甲基化限制的TF。研究人员在神经元中鉴定了几种因果TF，包括ONECUT1，它仅在基序变体上对甲基化敏感。无甲基化神经元中上调具有CRE基序的反转录转座子可在没有DNA甲基化的情况下通过CREB1甲基化激活。该研究揭示了体内甲基化敏感的TFs是被甲基化直接抑制而非MBD蛋白介导的间接抑制，这是甲基化介导调控区域和重复序列抑制的主要机制。

据介绍，胞嘧啶甲基化有效沉默哺乳动物基因组富含CpG的基因和重复序列调控区域。尚不清楚直接抑制转录因子结合或通过招募MBD蛋白发挥间接抑制在转录调控中所占的比重。

附：英文原文

Title: Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation

Author: Kaluscha, Sebastian, Domcke, Silvia, Wirbelauer, Christiane, Stadler, Michael B., Durdu, Sevi, Burger, Lukas, Schbeler, Dirk

Issue&Volume: 2022-12-05

Abstract: Cytosine methylation efficiently silences CpG-rich regulatory regions of genes and repeats in mammalian genomes. To what extent this entails direct inhibition of transcription factor (TF) binding versus indirect inhibition via recruitment of methyl-CpG-binding domain (MBD) proteins is unclear. Here we show that combinatorial genetic deletions of all four proteins with functional MBDs in mouse embryonic stem cells, derived neurons or a human cell line do not reactivate genes or repeats with methylated promoters. These do, however, become activated by methylation-restricted TFs if DNA methylation is removed. We identify several causal TFs in neurons, including ONECUT1, which is methylation sensitive only at a motif variant. Rampantly upregulated retrotransposons in methylation-free neurons feature a CRE motif, which activates them in the absence of DNA methylation via methylation-sensitive binding of CREB1. Our study reveals methylation-sensitive TFs in vivo and argues that direct inhibition, rather than indirect repression by the tested MBD proteins, is the prevailing mechanism of methylation-mediated repression at regulatory regions and repeats.

DOI: 10.1038/s41588-022-01241-6

Source: https://www.nature.com/articles/s41588-022-01241-6

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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