Gene regulatory network reconfiguration in direct lineage reprogramming.
Gene regulatory network reconfiguration in direct lineage reprogramming.
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DOI：
10.1016/j.stemcr.2022.11.010
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发表时间：
2023-01-10
影响因子：
5.9
通讯作者：
Morris SA
中科院分区：
文献类型：
--
作者：
Kamimoto K;Adil MT;Jindal K;Hoffmann CM;Kong W;Yang X;Morris SA
在直接谱系转换中，转录因子（TF）过表达重新配置基因调控网络（grn）以重编程细胞身份。我们之前开发了CellOracle，这是一种从单细胞转录组和表观基因组数据推断grn的计算方法。使用推断的grn， CellOracle模拟基因表达变化对TF扰动的响应，从而实现对网络重构的计算机询问。在这里，我们将CellOracle分析与成纤维细胞向诱导内胚层祖细胞（iEP）转化的谱系追踪结合起来，这是一种典型的直接重编程范例。通过将早期网络状态与重编程结果联系起来，我们揭示了成功和失败的命运转换背后的不同网络配置。通过对TF扰动的硅模拟，我们发现了新的因子来诱导细胞成功地转换它们的身份，揭示了AP-1亚基Fos与Hippo信号效应物Yap1的核心作用。总之，这些结果证明了CellOracle推断和解释细胞类型特异性GRN配置的有效性，为谱系重编程提供了新的机制见解。CellOracle解析直接谱系重编程中的基因调控网络重构谱系追踪成纤维细胞到内胚层祖细胞重编程揭示了早期网络变化计算机对网络重构的研究发现了新的重编程调控因子这些分析揭示了带有Hippo信号效应物Yap1的Fos在重编程中的作用。Morris及其同事将基因调控网络（GRN）分析和单细胞谱系追踪结合起来，剖析了成纤维细胞到诱导内胚层祖细胞重编程过程中细胞身份的变化。利用celloracle推断的grn进行计算机微扰模拟，揭示了重编程的新调控因子，以及Fos和Hippo信号效应因子Yap1在重编程细胞身份转换和维持中的作用。
In direct lineage conversion, transcription factor (TF) overexpression reconfigures gene regulatory networks (GRNs) to reprogram cell identity. We previously developed CellOracle, a computational method to infer GRNs from single-cell transcriptome and epigenome data. Using inferred GRNs, CellOracle simulates gene expression changes in response to TF perturbation, enabling in silico interrogation of network reconfiguration. Here, we combine CellOracle analysis with lineage tracing of fibroblast to induced endoderm progenitor (iEP) conversion, a prototypical direct reprogramming paradigm. By linking early network state to reprogramming outcome, we reveal distinct network configurations underlying successful and failed fate conversion. Via in silico simulation of TF perturbation, we identify new factors to coax cells into successfully converting their identity, uncovering a central role for the AP-1 subunit Fos with the Hippo signaling effector, Yap1. Together, these results demonstrate the efficacy of CellOracle to infer and interpret cell-type-specific GRN configurations, providing new mechanistic insights into lineage reprogramming. CellOracle dissects gene regulatory network reconfiguration in direct lineage reprogramming Lineage tracing fibroblast to endoderm progenitor reprogramming reveals early network changes In silico interrogation of network reconfiguration identifies new reprogramming regulators These analyses reveal a role for Fos with Hippo signaling effector, Yap1, in reprogramming In this article, Morris and colleagues combine gene regulatory network (GRN) analysis and single-cell lineage tracing to dissect changes in cell identity during fibroblast to induced endoderm progenitor reprogramming. In silico perturbation simulation using CellOracle-inferred GRNs reveals new regulators of reprogramming and a role for Fos and Hippo signaling effector, Yap1, in the conversion and maintenance of reprogrammed cell identity.
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