Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.
PLoS Comput Biol. 2019 Mar 1;15(3):e1006786. doi: 10.1371/journal.pcbi.1006786. eCollection 2019 Mar.
Many cellular responses to surrounding cues require temporally concerted transcriptional regulation of multiple genes. In prokaryotic cells, a single-input-module motif with one transcription factor regulating multiple target genes can generate coordinated gene expression. In eukaryotic cells, transcriptional activity of a gene is affected by not only transcription factors but also the epigenetic modifications and three-dimensional chromosome structure of the gene. To examine how local gene environment and transcription factor regulation are coupled, we performed a combined analysis of time-course RNA-seq data of TGF-β treated MCF10A cells and related epigenomic and Hi-C data. Using Dynamic Regulatory Events Miner (DREM), we clustered differentially expressed genes based on gene expression profiles and associated transcription factors. Genes in each class have similar temporal gene expression patterns and share common transcription factors. Next, we defined a set of linear and radial distribution functions, as used in statistical physics, to measure the distributions of genes within a class both spatially and linearly along the genomic sequence. Remarkably, genes within the same class despite sometimes being separated by tens of million bases (Mb) along genomic sequence show a significantly higher tendency to be spatially close despite sometimes being separated by tens of Mb along the genomic sequence than those belonging to different classes do. Analyses extended to the process of mouse nervous system development arrived at similar conclusions. Future studies will be able to test whether this spatial organization of chromosomes contributes to concerted gene expression.
许多细胞对周围环境线索的反应需要多个基因的转录调控在时间上协调一致。在原核细胞中，一个转录因子调节多个靶基因的单一输入模块基序可以产生协调的基因表达。在真核细胞中，基因的转录活性不仅受转录因子的影响，还受基因的表观遗传修饰和三维染色体结构的影响。为了研究局部基因环境和转录因子调节如何耦合，我们对 TGF-β 处理的 MCF10A 细胞的时间过程 RNA-seq 数据以及相关的表观基因组和 Hi-C 数据进行了综合分析。使用动态调节事件挖掘器（DREM），我们根据基因表达谱和相关转录因子对差异表达基因进行聚类。每个类别的基因具有相似的时间基因表达模式，并共享共同的转录因子。接下来，我们定义了一组线性和径向分布函数，如统计物理学中使用的那样，用于测量类内基因在空间和线性上沿基因组序列的分布。值得注意的是，即使在基因组序列上有时相隔数千万个碱基（Mb），同一类别的基因也表现出显著更高的空间接近倾向，尽管它们在基因组序列上有时相隔数十 Mb。对小鼠神经系统发育过程的分析得出了类似的结论。未来的研究将能够测试这种染色体的空间组织是否有助于协调基因表达。
