环境基因组学与系统生物学分部Len A. Pennacchio研究小组在研究中取得进展。他们的最新研究提出了人类增强子诱变敏感性的体内定位。相关论文于2025年6月18日发表在《自然》杂志上。

在这里，课题组在体内测定了人类发育增强剂对诱变的功能敏感性。在发育中的大脑、心脏、肢体和面部有活性的7个增强子上定位，研究小组为超过260个突变的增强子等位基因创造了1700多只转基因小鼠。12碱基对块的系统突变集体改变每个增强子的每个序列特征至少一次。课题组人员发现69%的基因块是正常体内活动所必需的，突变通常导致功能的丧失（60%）而不是获得（9%）。利用预测模型，研究人员在碱基对分辨率上标注了关键核苷酸。这些机器学习模型预测的绝大多数基元（88%）与体内功能的变化相吻合，并且模型显示出相当高的灵敏度，识别了所有功能块的59%。综上所述，他们的结果表明，人类增强子包含高密度的序列特征，这些特征是其正常体内功能所必需的，并为进一步探索人类增强子逻辑提供了丰富的阻力。

据介绍，远距离促进剂对人类发育至关重要。然而，他们对其功能序列特征的有限理解阻碍了对疾病中增强子突变的解释。

附：英文原文

Title: In vivo mapping of mutagenesis sensitivity of human enhancers

Author: Kosicki, Michael, Zhang, Boyang, Hecht, Vivian, Pampari, Anusri, Cook, Laura E., Slaven, Neil, Akiyama, Jennifer A., Plajzer-Frick, Ingrid, Novak, Catherine S., Kato, Momoe, Tran, Stella, Hunter, Riana D., von Maydell, Kianna, Barton, Sarah, Beckman, Erik, Zhu, Yiwen, Dickel, Diane E., Kundaje, Anshul, Visel, Axel, Pennacchio, Len A.

Issue&Volume: 2025-06-18

Abstract: Distant-acting enhancers are central to human development1. However, our limited understanding of their functional sequence features prevents the interpretation of enhancer mutations in disease2. Here we determined the functional sensitivity to mutagenesis of human developmental enhancers in vivo. Focusing on seven enhancers that are active in the developing brain, heart, limb and face, we created over 1,700 transgenic mice for over 260 mutagenized enhancer alleles. Systematic mutation of 12-base-pair blocks collectively altered each sequence feature in each enhancer at least once. We show that 69% of all blocks are required for normal in vivo activity, with mutations more commonly resulting in loss (60%) than in gain (9%) of function. Using predictive modelling, we annotated critical nucleotides at the base-pair resolution. The vast majority of motifs predicted by these machine learning models (88%) coincided with changes in in vivo function, and the models showed considerable sensitivity, identifying 59% of all functional blocks. Taken together, our results reveal that human enhancers contain a high density of sequence features that are required for their normal in vivo function and provide a rich resource for further exploration of human enhancer logic.

DOI: 10.1038/s41586-025-09182-w

Source: https://www.nature.com/articles/s41586-025-09182-w