Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Mol Syst Biol. 2012;8:604. doi: 10.1038/msb.2012.35.
Gene expression patterns can diverge between species due to changes in a gene's regulatory DNA or changes in the proteins, e.g., transcription factors (TFs), that regulate the gene. We developed a modeling framework to uncover the sources of expression differences in blastoderm embryos of three Drosophila species, focusing on the regulatory circuit controlling expression of the hunchback (hb) posterior stripe. Using this framework and cellular-resolution expression measurements of hb and its regulating TFs, we found that changes in the expression patterns of hb's TFs account for much of the expression divergence. We confirmed our predictions using transgenic D. melanogaster lines, which demonstrate that this set of orthologous cis-regulatory elements (CREs) direct similar, but not identical, expression patterns. We related expression pattern differences to sequence changes in the CRE using a calculation of the CRE's TF binding site content. By applying this calculation in both the transgenic and endogenous contexts, we found that changes in binding site content affect sensitivity to regulating TFs and that compensatory evolution may occur in circuit components other than the CRE.
由于基因的调控 DNA 发生变化或调节基因的蛋白质（例如转录因子 (TFs)）发生变化，基因表达模式可能会在物种之间出现差异。我们开发了一种建模框架，以揭示三种果蝇胚胎胚盘的表达差异的来源，重点是调控 hunchback (hb) 后条纹表达的调控回路。使用该框架和 hb 及其调节 TFs 的细胞分辨率表达测量，我们发现 hb 的 TF 表达模式的变化解释了大部分表达差异。我们使用转基因 D. melanogaster 系验证了我们的预测，这些系表明这组同源顺式调控元件 (CREs) 指导相似但不完全相同的表达模式。我们使用 CRE 的 TF 结合位点含量的计算将表达模式差异与 CRE 中的序列变化联系起来。通过在转基因和内源性环境中应用此计算，我们发现结合位点含量的变化会影响对调节 TF 的敏感性，并且除了 CRE 之外，回路组件可能会发生补偿性进化。
