巴塞罗那科技学院Lars Velten研究团队在研究中取得进展。他们揭示了造血中细胞状态特异性增强剂的设计原则。相关论文发表在2025年5月8日出版的《细胞》杂志上。

研究小组对64,400个完全合成的DNA序列进行了表征，以自下而上地剖析血液干细胞向七种髓系分化背景下细胞状态特异性增强子的设计原则。在38个TF的结合位点及其成对相互作用中，该研究团队发现相同的位点显示出抑制和激活功能，这是细胞状态、位点组合或仅仅预测TF在增强子上的占用的结果。令人惊讶的是，激活位点的组合经常相互中和或获得抑制功能。这些负协同作用将TF表达的数量失衡转化为二元活性模式。该课题组利用这一原理从头开始自动创建具有特异性的造血祖细胞状态组合的增强子。

据悉，在细胞分化过程中，增强子将转录因子（TF）的重叠梯度转化为高度特异性的基因表达模式。然而，调控DNA的巨大复杂性阻碍了对潜在顺式调控规则的识别。

附：英文原文

Title: Design principles of cell-state-specific enhancers in hematopoiesis

Author: Robert Frmel, Julia Rühle, Aina Bernal Martinez, Chelsea Szu-Tu, Felix Pacheco Pastor, Rosa Martinez-Corral, Lars Velten

Issue&Volume: 2025-05-08

Abstract: During cellular differentiation, enhancers transform overlapping gradients of transcription factors (TFs) to highly specific gene expression patterns. However, the vast complexity of regulatory DNA impedes the identification of the underlying cis-regulatory rules. Here, we characterized 64,400 fully synthetic DNA sequences to bottom-up dissect design principles of cell-state-specific enhancers in the context of the differentiation of blood stem cells to seven myeloid lineages. Focusing on binding sites for 38 TFs and their pairwise interactions, we found that identical sites displayed both repressive and activating function as a consequence of cell state, site combinatorics, or simply predicted occupancy of a TF on an enhancer. Surprisingly, combinations of activating sites frequently neutralized one another or gained repressive function. These negative synergies convert quantitative imbalances in TF expression into binary activity patterns. We exploit this principle to automatically create enhancers with specificity to user-defined combinations of hematopoietic progenitor cell states from scratch.

DOI: 10.1016/j.cell.2025.04.017

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00449-0