Transcriptome Dynamics and Potential Roles of Sox6 in the Postnatal Heart.
Transcriptome Dynamics and Potential Roles of Sox6 in the Postnatal Heart.
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DOI：
10.1371/journal.pone.0166574
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hagiwara N
中科院分区：
文献类型：
--
作者：
An CI;Ichihashi Y;Peng J;Sinha NR;Hagiwara N
出生后的心脏经历高度协调的发育过程，最终形成成人心脏的复杂生理特性。出生后心脏发育的分子机制尽管具有重要的临床意义，但在很大程度上尚未探索。为了在器官水平上获得出生后心脏发育过程中基因表达动态变化的综合视图，使用新开发的生物信息学管道对新生至成年小鼠（P1，P7，P14，P30和P60）的出生后心脏进行时间序列转录组分析。我们确定了功能基因簇的主成分分析与自组织地图聚类，揭示了有组织的，离散的基因表达模式，对应的生物功能与新生儿，青少年和成人阶段的出生后心脏发育。使用加权基因共表达网络分析与自举推断这些功能基因簇中的每一个，高度稳健的枢纽基因被鉴定出，其可能在调节共表达的功能性连锁基因的表达中起关键作用。此外，受转录因子Sox 6在骨骼肌功能成熟中的作用的启发，研究了Sox 6在出生后心肌成熟中的作用。Sox6敲除（KO）和对照心脏之间的差异表达转录组分析发现，Sox6 KO心脏中出生后第7天（P7）参与细胞增殖的基因显著上调。通过检测P7 Sox6 KO心脏中的有丝分裂活性细胞验证了该结果。目前的报告提供了一个框架，复杂的分子过程的出生后心脏发育，从而使系统解剖的发育退化中观察到的压力和失败的成人心脏。
The postnatal heart undergoes highly coordinated developmental processes culminating in the complex physiologic properties of the adult heart. The molecular mechanisms of postnatal heart development remain largely unexplored despite their important clinical implications. To gain an integrated view of the dynamic changes in gene expression during postnatal heart development at the organ level, time-series transcriptome analyses of the postnatal hearts of neonatal through adult mice (P1, P7, P14, P30, and P60) were performed using a newly developed bioinformatics pipeline. We identified functional gene clusters by principal component analysis with self-organizing map clustering which revealed organized, discrete gene expression patterns corresponding to biological functions associated with the neonatal, juvenile and adult stages of postnatal heart development. Using weighted gene co-expression network analysis with bootstrap inference for each of these functional gene clusters, highly robust hub genes were identified which likely play key roles in regulating expression of co-expressed, functionally linked genes. Additionally, motivated by the role of the transcription factor Sox6 in the functional maturation of skeletal muscle, the role of Sox6 in the postnatal maturation of cardiac muscle was investigated. Differentially expressed transcriptome analyses between Sox6 knockout (KO) and control hearts uncovered significant upregulation of genes involved in cell proliferation at postnatal day 7 (P7) in the Sox6 KO heart. This result was validated by detecting mitotically active cells in the P7 Sox6 KO heart. The current report provides a framework for the complex molecular processes of postnatal heart development, thus enabling systematic dissection of the developmental regression observed in the stressed and failing adult heart.
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