The McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
The McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Cell Stem Cell. 2022 Oct 6;29(10):1491-1504.e9. doi: 10.1016/j.stem.2022.09.006.
Direct reprogramming has revolutionized the fields of stem cell biology and regenerative medicine. However, the common mechanisms governing how reprogramming cells undergo transcriptome and epigenome remodeling (i.e., regulatome remodeling) have not been investigated. Here, by characterizing early changes in the regulatome of three different types of direct reprogramming, we identify lineage-specific features as well as common regulatory transcription factors. Of particular interest, we discover that the neuronal factor Ascl1 possesses cross-lineage potential; together with Mef2c, it drives efficient cardiac reprogramming toward a mature and induced cardiomyocyte phenotype. Through ChIP-seq and RNA-seq, we find that MEF2C drives the shift in ASCL1 binding away from neuronal genes toward cardiac genes, guiding their co-operative epigenetic and transcription activities. Together, these findings demonstrate the existence of common regulators of different direct reprogramming and argue against the premise that transcription factors possess only lineage-specific capabilities for altering cell fate - the basic premise used to develop direct reprogramming approaches.
直接重编程已经彻底改变了干细胞生物学和再生医学领域。然而，目前还没有研究哪些共同的机制控制着细胞在转录组和表观基因组重塑（即调控组重塑）过程中发生变化。在这里，我们通过对三种不同类型的直接重编程早期调控组的特征进行分析，确定了谱系特异性特征和共同的调控转录因子。特别有趣的是，我们发现神经元因子 Ascl1 具有跨谱系的潜力；它与 Mef2c 一起，能够高效地将心脏细胞重编程为成熟的诱导性心肌细胞表型。通过 ChIP-seq 和 RNA-seq，我们发现 MEF2C 驱动 ASCL1 结合从神经元基因向心脏基因的转变，指导它们的协同表观遗传和转录活性。总之，这些发现表明不同直接重编程之间存在共同的调控因子，这也反驳了转录因子只具有改变细胞命运的谱系特异性能力的观点——这种观点是开发直接重编程方法的基本前提。
