Mann Richard S, Lelli Katherine M, Joshi Rohit
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
Curr Top Dev Biol. 2009;88:63-101. doi: 10.1016/S0070-2153(09)88003-4.
Hox proteins are well known for executing highly specific functions in vivo, but our understanding of the molecular mechanisms underlying gene regulation by these fascinating proteins has lagged behind. The premise of this review is that an understanding of gene regulation-by any transcription factor-requires the dissection of the cis-regulatory elements that they act upon. With this goal in mind, we review the concepts and ideas regarding gene regulation by Hox proteins and apply them to a curated list of directly regulated Hox cis-regulatory elements that have been validated in the literature. Our analysis of the Hox-binding sites within these elements suggests several emerging generalizations. We distinguish between Hox cofactors, proteins that bind DNA cooperatively with Hox proteins and thereby help with DNA-binding site selection, and Hox collaborators, proteins that bind in parallel to Hox-targeted cis-regulatory elements and dictate the sign and strength of gene regulation. Finally, we summarize insights that come from examining five X-ray crystal structures of Hox-cofactor-DNA complexes. Together, these analyses reveal an enormous amount of flexibility into how Hox proteins function to regulate gene expression, perhaps providing an explanation for why these factors have been central players in the evolution of morphological diversity in the animal kingdom.
Hox蛋白在体内执行高度特异性功能是众所周知的，但我们对这些迷人蛋白质调控基因的分子机制的理解却滞后了。本综述的前提是，要理解任何转录因子对基因的调控，都需要剖析它们作用的顺式调控元件。出于这一目的，我们回顾了有关Hox蛋白调控基因的概念和观点，并将其应用于文献中已得到验证的直接受调控的Hox顺式调控元件的精选列表。我们对这些元件内Hox结合位点的分析提出了几个新出现的普遍规律。我们区分了Hox辅因子（与Hox蛋白协同结合DNA从而帮助选择DNA结合位点的蛋白质）和Hox协同因子（与Hox靶向的顺式调控元件平行结合并决定基因调控的正负和强度的蛋白质）。最后，我们总结了通过研究Hox-辅因子-DNA复合物的五个X射线晶体结构所获得的见解。这些分析共同揭示了Hox蛋白在调控基因表达方面具有极大的灵活性，这或许可以解释为什么这些因子在动物王国形态多样性的进化中一直是核心参与者。
