Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK.
The Alan Turing Institute for Data Science, British Library, 96 Euston Rd, Kings Cross, London, NW1 2DB, UK.
Genome Biol. 2018 Oct 25;19(1):174. doi: 10.1186/s13059-018-1558-2.
Transcription factor (TF) binding to regulatory DNA sites is a key determinant of cell identity within multi-cellular organisms and has been studied extensively in relation to site affinity and chromatin modifications. There has been a strong focus on the inference of TF-gene regulatory networks and TF-TF physical interaction networks. Here, we present a third type of TF network, the spatial network of co-localized TF binding sites within the three-dimensional genome.
Using published canonical Hi-C data and single-cell genome structures, we assess the spatial proximity of a genome-wide array of potential TF-TF co-localizations in human and mouse cell lines. For individual TFs, the abundance of occupied binding sites shows a positive correspondence with their clustering in three dimensions, and this is especially apparent for weak TF binding sites and at enhancer regions. An analysis between different TF proteins identifies significantly proximal pairs, which are enriched in reported physical interactions. Furthermore, clustering of different TFs based on proximity enrichment identifies two partially segregated co-localization sub-networks, involving different TFs in different cell types. Using data from both human lymphoblastoid cells and mouse embryonic stem cells, we find that these sub-networks are enriched within, but not exclusive to, different chromosome sub-compartments that have been identified previously in Hi-C data.
This suggests that the association of TFs within spatial networks is closely coupled to gene regulatory networks. This applies to both differentiated and undifferentiated cells and is a potential causal link between lineage-specific TF binding and chromosome sub-compartment segregation.
转录因子（TF）与调控 DNA 位点的结合是多细胞生物中细胞身份的关键决定因素，并且已经在与位点亲和力和染色质修饰相关的方面进行了广泛的研究。人们强烈关注于推断 TF-基因调控网络和 TF-TF 物理相互作用网络。在这里，我们提出了第三种 TF 网络，即三维基因组中共同定位 TF 结合位点的空间网络。
使用已发表的规范 Hi-C 数据和单细胞基因组结构，我们评估了人类和小鼠细胞系中全基因组范围内潜在 TF-TF 共定位的空间接近程度。对于单个 TF，占据结合位点的丰度与其在三维空间中的聚类呈正相关，而对于弱 TF 结合位点和增强子区域尤其如此。不同 TF 蛋白之间的分析确定了显著接近的对，这些对在报道的物理相互作用中富集。此外，基于接近富集对不同 TF 的聚类确定了两个部分分离的共定位子网络，涉及不同细胞类型中的不同 TF。使用来自人类淋巴母细胞和小鼠胚胎干细胞的数据，我们发现这些子网络在 Hi-C 数据中先前已经鉴定出的不同染色体亚区室中富集，但并非排他性富集。
这表明空间网络中 TF 的关联与基因调控网络密切相关。这适用于分化和未分化细胞，并且是谱系特异性 TF 结合与染色体亚区室分离之间的潜在因果关系。
