Zhu Xiusheng, Huang Lei, Li Guoli, Deng Biao, Wang Xiaoxiao, Yang Hu, Zhang Yuanyuan, Wen Qiuhan, Wang Chao, Zhang Jingshu, Zhao Yunxiang, Li Kui, Liu Yuwen
Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, 518124, China.
State Key Laboratory of Genetic Resources and Evolution, Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
Adv Sci (Weinh). 2025 May;12(18):e2408839. doi: 10.1002/advs.202408839. Epub 2025 Mar 20.
The majority of the mouse genome is composed of non-coding regions, which harbor numerous regulatory sequences essential for gene regulation. While extensive research focuses on enhancers that activate gene expression, the role of silencers that repress gene expression remains less explored. In this study, the first genome-wide identification of silencers in the mouse genome is conducted. In mouse embryonic fibroblasts (MEFs) and embryonic stem cells (mESCs), 89 596 and 115 165 silencers are identified, respectively. These silencers are ubiquitously distributed across the genome and are predominantly associated with low-expression genes. Additionally, these silencers are mainly cell-specific and function by binding to repressive transcription factors (TFs). Further, these silencers are notably enriched with the histone modification H3K9me3. It is observed that the transformation between dual-function silencers and enhancers is correlated with intracellular transcription factor concentrations, accompanied by changes in epigenetic modifications. In terms of biological effects, we have identified silencers that can enhance the induction efficiency of MEFs and influence the pluripotency of mESCs. Collectively, this work offers the first comprehensive silencer landscape in the mouse genome and provides strong evidence for the role of silencers in the induction of induced pluripotent stem cells (iPSCs).
小鼠基因组的大部分由非编码区域组成，这些区域含有许多对基因调控至关重要的调控序列。虽然广泛的研究集中在激活基因表达的增强子上，但抑制基因表达的沉默子的作用仍较少被探索。在这项研究中，首次在小鼠基因组中进行了全基因组范围的沉默子鉴定。在小鼠胚胎成纤维细胞（MEF）和胚胎干细胞（mESC）中，分别鉴定出89596个和115165个沉默子。这些沉默子在基因组中广泛分布，主要与低表达基因相关。此外，这些沉默子主要具有细胞特异性，并通过与抑制性转录因子（TF）结合发挥作用。进一步研究发现，这些沉默子显著富集组蛋白修饰H3K9me3。观察到双功能沉默子和增强子之间的转变与细胞内转录因子浓度相关，并伴随着表观遗传修饰的变化。在生物学效应方面，我们鉴定出了能够提高MEF诱导效率并影响mESC多能性的沉默子。总的来说，这项工作提供了小鼠基因组中首个全面的沉默子图谱，并为沉默子在诱导多能干细胞（iPSC）诱导过程中的作用提供了有力证据。
