Integrative Program for Biological and Genome Sciences, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Dev Cell. 2019 Apr 22;49(2):235-250.e7. doi: 10.1016/j.devcel.2019.03.002. Epub 2019 Apr 4.
The molecular basis of how animals integrate metabolic, developmental, and environmental information before committing resources to reproduction is an unresolved issue in developmental biology. In C. elegans, adult animals reallocate fat stores from intestinal cells to the germline via low-density lipoprotein (LDL)-like particles to promote embryogenesis. Here, I demonstrate that two conserved homeodomain transcription factors, CEH-60/PBX and UNC-62/MEIS, coordinate a transcriptional network that supports reproduction while suppressing longevity and stress-response pathways. The CEH-60:UNC-62 heterodimer serves an unanticipated dual function in intestinal nuclei by directly activating the expression of lipoprotein genes while directly repressing stress-responsive genes. Consequently, ceh-60 mutants display fat storage defects, a dramatic lifespan extension, and hyper-activation of innate immunity genes. Finally, CEH-60 associates with PQM-1 at the DAF-16-associated element within the promoters of stress-responsive genes to control gene expression. Thus, CEH-60 governs an elaborate transcriptional network that balances stress responses and longevity against reproduction during developmental transitions.
动物在将资源投入繁殖之前整合代谢、发育和环境信息的分子基础是发育生物学中尚未解决的问题。在秀丽隐杆线虫中，成年动物通过类似于低密度脂蛋白 (LDL) 的颗粒将脂肪储存从肠细胞重新分配到生殖系，以促进胚胎发生。在这里，我证明了两个保守的同源域转录因子，CEH-60/PBX 和 UNC-62/MEIS，协调了一个支持生殖的转录网络，同时抑制了长寿和应激反应途径。CEH-60:UNC-62 异二聚体在肠核中具有意想不到的双重功能，它可以直接激活脂蛋白基因的表达，同时直接抑制应激反应基因。因此，ceh-60 突变体表现出脂肪储存缺陷、寿命显著延长和先天免疫基因的过度激活。最后，CEH-60 与 PQM-1 结合在应激反应基因启动子中的 DAF-16 相关元件内，以控制基因表达。因此，CEH-60 控制着一个复杂的转录网络，在发育转变期间平衡应激反应、长寿和生殖。
