Fate erasure logic of gene networks underlying direct neuronal conversion of somatic cells by microRNAs.

IF 7.5 1区 生物学 Q1 CELL BIOLOGY
Cell reports Pub Date : 2025-01-28 Epub Date: 2025-01-04 DOI:10.1016/j.celrep.2024.115153
Kitra Cates, Luorongxin Yuan, Yan Yang, Andrew S Yoo
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引用次数: 0

Abstract

Neurogenic microRNAs 9/9 and 124 (miR-9/9-124) drive the direct reprogramming of human fibroblasts into neurons with the initiation of the fate erasure of fibroblasts. However, whether the miR-9/9-124 fate erasure logic extends to the neuronal conversion of other somatic cell types remains unknown. Here, we uncover that miR-9/9-124 induces neuronal conversion of multiple cell types: dura fibroblasts, astrocytes, smooth muscle cells, and pericytes. We reveal the cell-type-specific and pan-somatic gene network erasure induced by miR-9/9-124, including cell cycle, morphology, and proteostasis gene networks. Leveraging these pan-somatic gene networks, we predict upstream regulators that may antagonize somatic fate erasure. Among the predicted regulators, we identify TP53 (p53), whose inhibition is sufficient to enhance neuronal conversion even in post-mitotic cells. This study extends miR-9/9-124 reprogramming to alternate somatic cells, reveals the pan-somatic gene network fate erasure logic of miR-9/9-124, and shows a neurogenic role for p53 inhibition in the miR-9/9-124 signaling cascade.

microrna直接介导体细胞神经元转化的基因网络的命运擦除逻辑。
神经源性microRNAs 9/9∗和124 (miR-9/9∗-124)驱动人类成纤维细胞直接重编程成神经元,引发成纤维细胞的命运消除。然而,miR-9/9 * -124命运擦除逻辑是否延伸到其他体细胞类型的神经元转化仍然未知。在这里,我们发现miR-9/9 * -124诱导多种细胞类型的神经元转化:硬脑膜成纤维细胞、星形胶质细胞、平滑肌细胞和周细胞。我们揭示了miR-9/9 * -124诱导的细胞类型特异性和泛体细胞基因网络擦除,包括细胞周期,形态和蛋白酶抑制基因网络。利用这些泛体细胞基因网络,我们预测上游调控可能对抗体细胞命运消除。在预测的调节因子中,我们确定了TP53 (p53),其抑制足以增强即使在有丝分裂后细胞中的神经元转换。这项研究将miR-9/9∗-124重编程扩展到交替体细胞,揭示了miR-9/9∗-124的泛体细胞基因网络命运擦除逻辑,并显示了p53在miR-9/9∗-124信号级联中抑制的神经源性作用。
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来源期刊
Cell reports
Cell reports CELL BIOLOGY-
CiteScore
13.80
自引率
1.10%
发文量
1305
审稿时长
77 days
期刊介绍: Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.
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