Sahaf Naeini Alireza, Farooq Amna, Bjørås Magnar, Wang Junbai
Department of Pathology, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.
Department of Microbiology, Oslo University Hospital, Oslo, Norway.
Comput Struct Biotechnol J. 2020 Jun 2;18:1270-1286. doi: 10.1016/j.csbj.2020.05.024. eCollection 2020.
The human genome is regulated in a multi-dimensional way. While biophysical factors like Non-specific Transcription factor Binding Affinity (nTBA) act at DNA sequence level, other factors act above sequence levels such as histone modifications and 3-D chromosomal interactions. This multidimensionality of regulation requires many of these factors for a proper understanding of the regulatory landscape of the human genome. Here, we propose a new biophysical model for estimating nTBA. Integration of nTBA with chromatin modifications and chromosomal interactions, using a new Integrative Genome Analysis Pipeline (IGAP), reveals additive effects of nTBA to regulatory DNA sequences and identifies three types of genomic zones in the human genome (Inactive Genomic Zones, Poised Genomic Zones, and Active Genomic Zones). It also unveils a novel long distance gene regulatory model: chromosomal interactions reduce the physical distance between the high occupancy target (HOT) regions that results in high nTBA to DNA in the area, which in turn attract TFs to such regions with higher binding potential. These findings will help to elucidate the three-dimensional diffusion process that TFs use during their search for the right targets.
人类基因组以多维度方式受到调控。虽然诸如非特异性转录因子结合亲和力（nTBA）等生物物理因素在DNA序列水平起作用，但其他因素则在序列水平之上起作用，例如组蛋白修饰和三维染色体相互作用。这种调控的多维度性需要许多这些因素才能正确理解人类基因组的调控格局。在此，我们提出了一种用于估计nTBA的新生物物理模型。使用新的综合基因组分析管道（IGAP）将nTBA与染色质修饰和染色体相互作用相结合，揭示了nTBA对调控DNA序列的累加效应，并在人类基因组中识别出三种类型的基因组区域（无活性基因组区域、 poised基因组区域和活性基因组区域）。它还揭示了一种新的长距离基因调控模型：染色体相互作用减少了高占据靶点（HOT）区域之间的物理距离，这导致该区域对DNA具有高nTBA，进而吸引转录因子到具有更高结合潜力的此类区域。这些发现将有助于阐明转录因子在寻找正确靶点过程中所使用的三维扩散过程。
