Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology and Howard Hughes Medical Institute, Princeton University, Princeton, NJ 08544, USA.
Dev Cell. 2023 Dec 4;58(23):2789-2801.e5. doi: 10.1016/j.devcel.2023.10.001. Epub 2023 Oct 26.
Transcription factor combinations play a key role in shaping cellular identity. However, the precise relationship between specific combinations and downstream effects remains elusive. Here, we investigate this relationship within the context of the Drosophila eve locus, which is controlled by gap genes. We measure spatiotemporal levels of four gap genes in heterozygous and homozygous gap mutant embryos and correlate them with the striped eve activity pattern. Although changes in gap gene expression extend beyond the manipulated gene, the spatial patterns of Eve expression closely mirror canonical activation levels in wild type. Interestingly, some combinations deviate from the wild-type repertoire but still drive eve activation. Although in homozygous mutants some Eve stripes exhibit partial penetrance, stripes consistently emerge at reproducible positions, even with varying gap gene levels. Our findings suggest a robust molecular canalization of cell fates in gap mutants and provide insights into the regulatory constraints governing multi-enhancer gene loci.
转录因子组合在塑造细胞身份方面起着关键作用。然而，特定组合与下游效应之间的确切关系仍然难以捉摸。在这里，我们在果蝇 eve 基因座的背景下研究了这种关系，该基因座受间隙基因控制。我们测量了杂合和纯合间隙突变体胚胎中四个间隙基因的时空水平，并将其与条纹 eve 活性模式相关联。尽管间隙基因表达的变化超出了操纵基因的范围，但 Eve 表达的空间模式与野生型中的典型激活水平非常相似。有趣的是，一些组合偏离了野生型，但仍能驱动 eve 的激活。尽管在纯合突变体中，一些 Eve 条纹表现出部分穿透，但条纹始终出现在可重复的位置，即使间隙基因水平不同。我们的研究结果表明，在间隙突变体中，细胞命运具有稳健的分子渠道化，并为调控多增强子基因座的规则提供了见解。
