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免疫细胞命运转换过程中IRF8和FOS增强子对的协同和拮抗活性。

Synergistic and antagonistic activities of IRF8 and FOS enhancer pairs during an immune-cell fate switch.

作者信息

Klonizakis Antonios, Alcoverro-Bertran Marc, Massó Pere, Thomas Joanna, de Andrés-Aguayo Luisa, Wei Xiao, Varamogianni-Mamatsi Vassiliki, Nikolaou Christoforos, Graf Thomas

机构信息

Genome Biology Program, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003, Barcelona, Spain.

Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08005, Barcelona, Spain.

出版信息

EMBO J. 2025 Apr;44(7):2025-2055. doi: 10.1038/s44318-025-00380-w. Epub 2025 Feb 19.

DOI:10.1038/s44318-025-00380-w
PMID:39972074
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11961672/
Abstract

Cell fate instructive genes tend to be regulated by large clusters of enhancers. Whether and how individual enhancers within such clusters cooperate in regulating gene expression is poorly understood. We have previously developed a computational method, SEGCOND, which identifies hubs that we termed Putative Transcriptional Condensates (PTCs), consisting of enhancer clusters and associated target genes. Here, we use SEGCOND to identify PTCs in a CEBPA-induced B-cell-to-macrophage transdifferentiation system. We find that PTCs are enriched for highly expressed, lineage-restricted genes and associate with BRD4, a component of transcriptional condensates. Further, we performed single and combinatorial deletions of enhancers within two PTCs active during induced transdifferentiation, harboring IRF8 and FOS. Two enhancers within the IRF8 PTC were found to provide a backup mechanism when combined, safeguarding IRF8 expression and efficient transdifferentiation. Unexpectedly, two individual enhancers within the FOS PTC antagonize each other on day 1 of transdifferentiation, delaying the conversion of B-cells into macrophages and reducing FOS expression, while on day 7, they cooperate to increase FOS levels induced cells. Our results reveal complex, differentiation-stage-specific interactions between individual enhancers within enhancer clusters.

摘要

细胞命运决定基因往往受大量增强子簇调控。此类簇内的单个增强子如何以及是否协同调控基因表达，目前仍知之甚少。我们之前开发了一种计算方法SEGCOND，该方法可识别出我们称为假定转录凝聚物（PTC）的枢纽，其由增强子簇和相关靶基因组成。在此，我们使用SEGCOND在CEBPA诱导的B细胞向巨噬细胞转分化系统中识别PTC。我们发现，PTC富含高表达的、谱系受限的基因，并与转录凝聚物的一个组分BRD4相关。此外，我们对诱导转分化过程中活跃的两个含有IRF8和FOS的PTC内的增强子进行了单缺失和组合缺失。结果发现，IRF8 PTC内的两个增强子组合时可提供一种备用机制，保障IRF8表达和高效转分化。出乎意料的是，FOS PTC内的两个单个增强子在转分化第1天相互拮抗，延迟B细胞向巨噬细胞的转化并降低FOS表达，而在第7天，它们协同作用以提高FOS水平从而促进细胞分化。我们的结果揭示了增强子簇内单个增强子之间复杂的、分化阶段特异性的相互作用。

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本文引用的文献

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Transcriptional condensates: a blessing or a curse for gene regulation?转录凝聚物：对基因调控是福是祸？
Commun Biol. 2024 Feb 16;7(1):187. doi: 10.1038/s42003-024-05892-5.
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Super-enhancers include classical enhancers and facilitators to fully activate gene expression.超级增强子包括经典增强子和促进子，以充分激活基因表达。
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3D Enhancer-promoter networks provide predictive features for gene expression and coregulation in early embryonic lineages.
三维增强子-启动子网络为早期胚胎谱系中的基因表达和共调控提供预测特征。
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interactions in the locus regulate stage-dependent enhancer activation. 基因座中的相互作用调节阶段依赖性增强子激活。
Genes Dev. 2023 Apr 1;37(7-8):291-302. doi: 10.1101/gad.350339.122. Epub 2023 Mar 29.
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SEGCOND predicts putative transcriptional condensate-associated genomic regions by integrating multi-omics data.SEGCOND 通过整合多组学数据来预测假定的转录凝聚物相关基因组区域。
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WashU Epigenome Browser update 2022.WashU Epigenome Browser 更新 2022 版
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