Vanzan Ludovica, Soldati Hadrien, Ythier Victor, Anand Santosh, Braun Simon M G, Francis Nicole, Murr Rabih
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Nat Commun. 2021 Jun 7;12(1):3337. doi: 10.1038/s41467-021-23630-x.
Binding of mammalian transcription factors (TFs) to regulatory regions is hindered by chromatin compaction and DNA methylation of their binding sites. Nevertheless, pioneer transcription factors (PFs), a distinct class of TFs, have the ability to access nucleosomal DNA, leading to nucleosome remodelling and enhanced chromatin accessibility. Whether PFs can bind to methylated sites and induce DNA demethylation is largely unknown. Using a highly parallelized approach to investigate PF ability to bind methylated DNA and induce DNA demethylation, we show that the interdependence between DNA methylation and TF binding is more complex than previously thought, even within a select group of TFs displaying pioneering activity; while some PFs do not affect the methylation status of their binding sites, we identified PFs that can protect DNA from methylation and others that can induce DNA demethylation at methylated binding sites. We call the latter super pioneer transcription factors (SPFs), as they are seemingly able to overcome several types of repressive epigenetic marks. Finally, while most SPFs induce TET-dependent active DNA demethylation, SOX2 binding leads to passive demethylation, an activity enhanced by the co-binding of OCT4. This finding suggests that SPFs could interfere with epigenetic memory during DNA replication.
哺乳动物转录因子（TFs）与调控区域的结合会受到染色质压缩及其结合位点的DNA甲基化的阻碍。然而，先驱转录因子（PFs）作为一类独特的TFs，具有访问核小体DNA的能力，从而导致核小体重塑和染色质可及性增强。PFs是否能结合甲基化位点并诱导DNA去甲基化在很大程度上尚不清楚。我们采用高度并行的方法来研究PFs结合甲基化DNA并诱导DNA去甲基化的能力，结果表明，DNA甲基化与TF结合之间的相互依赖性比之前认为的更为复杂，即使在一组显示先驱活性的特定TFs中也是如此；虽然一些PFs不会影响其结合位点的甲基化状态，但我们鉴定出了能够保护DNA不被甲基化的PFs以及能够在甲基化结合位点诱导DNA去甲基化的PFs。我们将后者称为超级先驱转录因子（SPFs），因为它们似乎能够克服几种类型的抑制性表观遗传标记。最后，虽然大多数SPFs诱导依赖TET的活性DNA去甲基化，但SOX2的结合会导致被动去甲基化，这种活性会因OCT4的共同结合而增强。这一发现表明，SPFs可能会在DNA复制过程中干扰表观遗传记忆。
