心肌细胞成熟的转录图谱
Transcriptional Landscape of Cardiomyocyte Maturation.
作者信息
Uosaki Hideki, Cahan Patrick, Lee Dong I, Wang Songnan, Miyamoto Matthew, Fernandez Laviel, Kass David A, Kwon Chulan
机构信息
Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Johns Hopkins Institute for Cell Engineering, Baltimore, MD 21205, USA.
Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
出版信息
Cell Rep. 2015 Nov 24;13(8):1705-16. doi: 10.1016/j.celrep.2015.10.032. Epub 2015 Nov 12.
Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of the CM maturation that is subsequently required to generate adult myocytes remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs), which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStat(CM) that indexes CM maturation status. MatStat(CM) reveals that pluripotent-stem-cell-derived CMs mature early in culture but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation.
发育心脏病学数十年来的进展加深了我们对心脏发育早期阶段的理解，包括心肌细胞（CM）分化。然而，随后生成成年心肌细胞所需的CM成熟的调控机制仍然难以捉摸。在这里，我们分析了从早期胚胎心脏到成年心脏的200多个微阵列数据集，并鉴定出大量在成熟过程中表达逐渐且持续变化的基因。我们生成了一个整合基因表达、生物途径、转录调节因子和基因调控网络（GRN）的图谱，该图谱显示了在CM成熟过程中激活或抑制的离散关键转录调节因子和途径集合。我们开发了一个基于GRN的程序MatStat(CM)，用于索引CM成熟状态。MatStat(CM)显示，多能干细胞衍生的CM在培养早期成熟，但在胚胎后期停滞，关键转录因子调控异常。我们的研究为理解CM成熟提供了基础。
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