Institut de Génétique Humaine (UMR 9002), CNRS, 141, rue de la Cardonille, 34396 Montpellier, France.
Nucleic Acids Res. 2024 Sep 9;52(16):9360-9368. doi: 10.1093/nar/gkae694.
Our conception of gene regulation specificity has undergone profound changes over the last 20 years. Previously, regulators were considered to control few genes, recognized with exquisite specificity by a 'lock and key' mechanism. However, recently genome-wide exploration of regulator binding site occupancy (whether on DNA or RNA targets) revealed extensive lists of molecular targets for every studied regulator. Such poor biochemical specificity suggested that each regulator controls many genes, collectively contributing to biological phenotypes. Here, I propose a third model, whereby regulators' biological specificity is only partially due to 'lock and key' biochemistry. Rather, regulators affect many genes at the microscopic scale, but biological consequences for most interactions are attenuated at the mesoscopic scale: only a few regulatory events propagate from microscopic to macroscopic scale; others are made inconsequential by homeostatic mechanisms. This model is well supported by the microRNA literature, and data suggest that it extends to other regulators. It reconciles contradicting observations from biochemistry and comparative genomics on one hand and in vivo genetics on the other hand, but this conceptual unification is obscured by common misconceptions and counter-intuitive modes of graphical display. Profound understanding of gene regulation requires conceptual clarification, and better suited statistical analyses and graphical representation.
在过去的 20 年里，我们对基因调控特异性的认识发生了深刻的变化。以前，调控因子被认为只控制少数几个基因，通过“锁钥”机制精确识别。然而，最近对调控因子结合位点占据（无论是在 DNA 还是 RNA 靶标上）的全基因组探索揭示了每一个研究调控因子的大量分子靶标列表。这种较差的生化特异性表明，每个调控因子控制着许多基因，共同促成了生物学表型。在这里，我提出了第三个模型，即调控因子的生物学特异性部分归因于“锁钥”生化。相反，调控因子在微观尺度上影响许多基因，但大多数相互作用的生物学后果在介观尺度上被削弱：只有少数几个调控事件从微观尺度传播到宏观尺度；其他则通过体内平衡机制变得无关紧要。这个模型得到了 microRNA 文献的很好支持，并且数据表明它扩展到了其他调控因子。它调和了一方面来自生物化学和比较基因组学的矛盾观察，另一方面来自体内遗传学的矛盾观察，但这种概念上的统一被常见的误解和反直觉的图形显示方式所掩盖。对基因调控的深刻理解需要概念上的澄清，以及更合适的统计分析和图形表示。
