美国南加州大学Justin K. Ichida和麻省理工学院Kate E. Galloway团队最新研究发现，减缓转录和增殖之间的拮抗作用可以让几乎确定的细胞重编程发生。 该研究于2019年9月12日在线发表于《细胞—干细胞》。

通过成纤维细胞重编程为运动神经元和多个其它体细胞系的筛选，研究人员发现通过赋予细胞减轻转录和DNA复制之间固有拮抗作用的能力，可以克服重编程的表观遗传障碍。研究人员发现转录因子的过表达诱导异常高的转录效率，并且在重编程早期维持过度增殖细胞中的高转录和基因表达对于成功的谱系转化是至关重要的。然而，高转录阻碍了促进了重编程过程的DNA复制和细胞增殖。

研究人员鉴定了一种化学和生物学混合物，它通过激活拓扑异构酶显著增加了能够同时进行高转录和过度增殖的细胞数量。此外，研究表明，高转录、过度增殖细胞重编程效率提高100倍，这是几乎确定的重编程效率。因此，释放生物物理学约束克服了细胞重编程的分子障碍。

研究人员介绍，尽管细胞重编程能够产生用于疾病模拟和再生疗法的新细胞类型，但重编程仍然是罕见的细胞事件。

附：英文原文

Title: Mitigating Antagonism between Transcription and Proliferation Allows Near-Deterministic Cellular Reprogramming

Author: Kimberley N. Babos, Kate E. Galloway, Kassandra Kisler, Madison Zitting, Yichen Li, Yingxiao Shi, Brooke Quintino, Robert H. Chow, Berislav V. Zlokovic, Justin K. Ichida

Issue&Volume: 12 September 2019

Summary: 

Although cellular reprogramming enables the generation of new cell types for disease modeling and regenerative therapies, reprogramming remains a rare cellular event. By examining reprogramming of fibroblasts into motor neurons and multiple other somatic lineages, we find that epigenetic barriers to conversion can be overcome by endowing cells with the ability to mitigate an inherent antagonism between transcription and DNA replication. We show that transcription factor overexpression induces unusually high rates of transcription and that sustaining hypertranscription and transgene expression in hyperproliferative cells early in reprogramming is critical for successful lineage conversion. However, hypertranscription impedes DNA replication and cell proliferation, processes that facilitate reprogramming. We identify a chemical and genetic cocktail that dramatically increases the number of cells capable of simultaneous hypertranscription and hyperproliferation by activating topoisomerases. Further, we show that hypertranscribing, hyperproliferating cells reprogram at 100-fold higher, near-deterministic rates. Therefore, relaxing biophysical constraints overcomes molecular barriers to cellular reprogramming.

DOI: 10.1016/j.stem.2019.08.005

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30340-6