Liu Ziying, Kraus W Lee
The Laboratory of Signaling and Gene Expression, Cecil H. and Ida Green Center for Reproductive Biology Sciences and The Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8511, USA; Program in Genetics, Development, and Disease, Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
The Laboratory of Signaling and Gene Expression, Cecil H. and Ida Green Center for Reproductive Biology Sciences and The Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8511, USA; Program in Genetics, Development, and Disease, Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mol Cell. 2017 Feb 16;65(4):589-603.e9. doi: 10.1016/j.molcel.2017.01.017.
Pioneer transcription factors (TFs) function as genomic first responders, binding to inaccessible regions of chromatin to promote enhancer formation. The mechanism by which pioneer TFs gain access to chromatin remains an important unanswered question. Here we show that PARP-1, a nucleosome-binding protein, cooperates with intrinsic properties of the pioneer TF Sox2 to facilitate its binding to intractable genomic loci in embryonic stem cells. These actions of PARP-1 occur independently of its poly(ADP-ribosyl) transferase activity. PARP-1-dependent Sox2-binding sites reside in euchromatic regions of the genome with relatively high nucleosome occupancy and low co-occupancy by other transcription factors. PARP-1 stabilizes Sox2 binding to nucleosomes at suboptimal sites through cooperative interactions on DNA. Our results define intrinsic and extrinsic features that determine Sox2 pioneer activity. The conditional pioneer activity observed with Sox2 at a subset of binding sites may be a key feature of other pioneer TFs operating at intractable genomic loci.
先驱转录因子（TFs）作为基因组的首批响应者，与染色质难以接近的区域结合，以促进增强子的形成。先驱TFs进入染色质的机制仍是一个重要的未解决问题。在此，我们表明，一种核小体结合蛋白PARP-1与先驱TF Sox2的内在特性协同作用，以促进其在胚胎干细胞中与难处理的基因组位点结合。PARP-1的这些作用独立于其聚（ADP-核糖基）转移酶活性而发生。PARP-1依赖的Sox2结合位点位于基因组的常染色质区域，核小体占据率相对较高，其他转录因子的共占据率较低。PARP-1通过与DNA的协同相互作用，稳定Sox2在次优位点与核小体的结合。我们的结果定义了决定Sox2先驱活性的内在和外在特征。在一部分结合位点观察到的Sox2的条件性先驱活性可能是在难处理的基因组位点起作用的其他先驱TFs的一个关键特征。
