Research Group Genome Organization & Function, Deutsches Krebsforschungszentrum-DKFZ & BioQuant, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Methods. 2013 Jul 15;62(1):26-38. doi: 10.1016/j.ymeth.2013.03.011. Epub 2013 Mar 21.
The eukaryotic genome is organized in a chain of nucleosomes that consist of 145-147 bp of DNA wrapped around a histone octamer protein core. Binding of transcription factors (TF) to nucleosomal DNA is frequently impeded, which makes it a challenging task to calculate TF occupancy at a given regulatory genomic site for predicting gene expression. Here, we review methods to calculate TF binding to DNA in the presence of nucleosomes. The main theoretical problems are (i) the computation speed that is becoming a bottleneck when partial unwrapping of DNA from the nucleosome is considered, (ii) the perturbation of the binding equilibrium by the activity of ATP-dependent chromatin remodelers, which translocate nucleosomes along the DNA, and (iii) the model parameterization from high-throughput sequencing data and fluorescence microscopy experiments in living cells. We discuss strategies that address these issues to efficiently compute transcription factor binding in chromatin.
真核生物基因组组织在核小体链中，核小体由 145-147bp 的 DNA 缠绕在组蛋白八聚体蛋白核心周围。转录因子（TF）与核小体 DNA 的结合常常受到阻碍，这使得计算给定调控基因组位点的 TF 占有率以预测基因表达成为一项具有挑战性的任务。在这里，我们回顾了在存在核小体的情况下计算 TF 与 DNA 结合的方法。主要的理论问题是：（i）当考虑从核小体上部分解开 DNA 时，计算速度成为瓶颈；（ii）由 ATP 依赖性染色质重塑酶的活性引起的结合平衡的扰动，这些酶沿 DNA 转运核小体；（iii）从高通量测序数据和活细胞中的荧光显微镜实验进行模型参数化。我们讨论了应对这些问题的策略，以有效地计算染色质中的转录因子结合。
