Small compound-based direct cell conversion with combinatorial optimization of pathway regulations
Small compound-based direct cell conversion with combinatorial optimization of pathway regulations
复制标题
基于小型化合物的直接细胞转化与途径调控的组合优化
DOI：
10.1093/bioinformatics/btac475
复制
发表时间：
2022
期刊：
影响因子：
5.8
通讯作者：
Yamanishi Yoshihiro
中科院分区：
文献类型：
--
作者：
Nakamura Toru;Iwata Michio;Hamano Momoko;Eguchi Ryohei;Takeshita Jun-ichi;Yamanishi Yoshihiro
MotivationDirect细胞转化，即直接重编程（DR），是一项创新技术，无需绕过诱导多能干细胞，直接将源细胞转化为靶细胞。使用小化合物（例如药物）进行DR可以帮助避免基因转染引起的致癌风险；然而，由于组合爆炸，通过实验识别小化合物仍然具有挑战性。结果在本文中，我们提出了一种新的计算方法 COMPRENDRE（直接重编程路径调节的组合优化），以阐明基于小化合物的 DR 机制并预测用于 DR 的小化合物的新组合。我们估计了诱导 DR 的小化合物的潜在靶蛋白，并确定了一组涉及 DR 的靶途径。我们发现了多种 DR 相关途径，这些途径以前从未报道过从成纤维细胞诱导神经元或心肌细胞。为了克服组合爆炸问题，我们开发了一种模拟退火算法的变体，以识别可以调节 DR 相关途径的最佳化合物集。因此，所提出的方法能够用更少的化合物预测新的 DR 诱导候选组合，并成功地复制经过实验验证的化合物，诱导成纤维细胞直接转化为神经元或心肌细胞。所提出的方法预计对再生医学的实际应用有用。可用性和实施支持当前研究的代码可在 http://labo.bio.kyutech.ac.jp/~yamani/comprendre 上获得。补充信息补充数据可在 Bioinformaticsonline 上获得。
MotivationDirect cell conversion, direct reprogramming (DR), is an innovative technology that directly converts source cells to target cells without bypassing induced pluripotent stem cells. The use of small compounds (e.g. drugs) for DR can help avoid carcinogenic risk induced by gene transfection; however, experimentally identifying small compounds remains challenging because of combinatorial explosion.ResultsIn this article, we present a new computational method, COMPRENDRE (combinatorial optimization of pathway regulations for direct reprograming), to elucidate the mechanism of small compound-based DR and predict new combinations of small compounds for DR. We estimated the potential target proteins of DR-inducing small compounds and identified a set of target pathways involving DR. We identified multiple DR-related pathways that have not previously been reported to induce neurons or cardiomyocytes from fibroblasts. To overcome the problem of combinatorial explosion, we developed a variant of a simulated annealing algorithm to identify the best set of compounds that can regulate DR-related pathways. Consequently, the proposed method enabled to predict new DR-inducing candidate combinations with fewer compounds and to successfully reproduce experimentally verified compounds inducing the direct conversion from fibroblasts to neurons or cardiomyocytes. The proposed method is expected to be useful for practical applications in regenerative medicine.Availability and implementationThe code supporting the current study is available at the http://labo.bio.kyutech.ac.jp/~yamani/comprendre.Supplementary informationSupplementary data are available atBioinformaticsonline.