Cui Miao, Vielmas Erika, Davidson Eric H, Peter Isabelle S
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Cell Rep. 2017 Apr 11;19(2):364-374. doi: 10.1016/j.celrep.2017.03.039.
Gene expression in different spatial domains is often controlled by separate cis-regulatory modules (CRMs), but regulatory states determining CRM activity are not only distinct in space, they also change continuously during developmental time. Here, we systematically analyzed the regulatory sequences controlling hox11/13b expression and identified a single CRM required throughout embryonic gut development. We show that within this CRM, distinct sets of binding sites recognizing Ets, Tcf, and homeodomain transcription factors control the dynamic spatial expression of hox11/13b in each developmental phase. Several binding sites execute multiple, sometimes contradictory, regulatory functions, depending on the temporal and spatial regulatory context. In addition, we identified a nearby second CRM operating in inter-modular AND logic with the first CRM to control hox11/13b expression in hindgut endoderm. Our results suggest a mechanism for continuous gene expression in response to changing developmental network functions that depends on sequential combinatorial regulation of individual CRMs.
不同空间域中的基因表达通常由独立的顺式调控模块（CRM）控制，但决定CRM活性的调控状态不仅在空间上不同，在发育过程中也会持续变化。在这里，我们系统地分析了控制hox11/13b表达的调控序列，并确定了整个胚胎肠道发育过程中所需的单个CRM。我们表明，在这个CRM中，识别Ets、Tcf和同源域转录因子的不同结合位点集控制着hox11/13b在每个发育阶段的动态空间表达。几个结合位点根据时间和空间调控背景执行多种、有时相互矛盾的调控功能。此外，我们在附近发现了第二个CRM，它与第一个CRM以模块间“与”逻辑运行，以控制后肠内胚层中hox11/13b的表达。我们的结果提出了一种机制，通过对单个CRM的顺序组合调控，响应不断变化的发育网络功能来实现持续的基因表达。
