鉴定和干扰 CTCF 介导的染色质相互作用以增强成肌细胞的转分化。
Characterization and perturbation of CTCF-mediated chromatin interactions for enhancing myogenic transdifferentiation.
机构信息
Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China; College of Animal Science and Technology, Shandong Agricultural University, Taian, China.
Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China.
出版信息
Cell Rep. 2022 Aug 16;40(7):111206. doi: 10.1016/j.celrep.2022.111206.
Expression of key transcription factors can induce transdifferentiation in somatic cells; however, this conversion is usually incomplete due to undefined intrinsic barriers. Here, we employ MyoD-induced transdifferentiation of fibroblasts as a model to illustrate the chromatin structures that impede the cell-fate transition. Focusing on the three-dimensional (3D) chromatin interactions, we show that MyoD directly establishes chromatin loops to activate myogenic transcriptional program. Similarly, dynamic changes of CTCF-mediated chromatin interactions are favorable for fibroblast-to-myoblast conversion. However, a substantial portion of CTCF-mediated chromatin interactions remain stable, and the associated genes are steady in expression and enriched for fibroblast function that may restrict cell-identity transformation. Temporal CTCF depletion can interrupt the resistant chromatin loops to enhance myogenic transdifferentiation in mice, pig, and chicken fibroblasts. Therefore, during induced transdifferentiation, the transcription factor can directly reorganize the 3D chromatin interactions, and perturbation of CTCF-mediated genome topology may resolve the limitations of cell fate transitions.
关键转录因子的表达可以诱导体细胞的转分化；然而，由于内在定义不明确的障碍，这种转化通常是不完全的。在这里，我们采用 MyoD 诱导的成纤维细胞转分化作为模型，来说明阻碍细胞命运转变的染色质结构。我们专注于三维（3D）染色质相互作用，表明 MyoD 可以直接建立染色质环来激活成肌转录程序。同样，CTCF 介导的染色质相互作用的动态变化有利于成纤维细胞向成肌细胞的转化。然而，大量 CTCF 介导的染色质相互作用仍然保持稳定，并且相关基因的表达稳定，并且富含成纤维细胞功能，这可能限制细胞身份的转变。在小鼠、猪和鸡成纤维细胞中，瞬时 CTCF 耗竭可以中断抗性染色质环，从而增强成肌的转分化。因此，在诱导的转分化过程中，转录因子可以直接重组三维染色质相互作用，而 CTCF 介导的基因组拓扑结构的干扰可能会解决细胞命运转变的限制。
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