Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury
Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury
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DOI：
10.1161/circulationaha.117.027832
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发表时间：
2017-10-10
期刊：
影响因子：
37.8
通讯作者：
Van Rooij, Eva
中科院分区：
文献类型：
--
作者：
Lacraz, Gregory P. A.;Junker, Jan Philipp;Van Rooij, Eva
背景：心脏缺血损伤可引起病理性重构反应，最终导致心力衰竭。对与心脏重塑不同方面相关的分子信号通路的详细机制见解将有助于确定新的治疗靶点。方法：尽管对病变组织的全基因组转录组分析极大地促进了我们对驱动心脏病理变化的调控网络的理解，但由于信号来自组织匀浆，这种方法一直处于不利地位。在这里，我们使用tomo-seq获得了从梗死区域到远程的高空间分辨率的全基因组基因表达特征，以确定心脏重构的新调控因子。来自缺血性心脏病患者的心脏组织样本被用来验证我们的发现。结果：通过高空间分辨率追踪梗死心脏的转录差异使我们能够识别具有可比表达谱的基因簇。空间分布模式表明，参与心脏重构特定方面的基因表达变化分离，如纤维化、心肌细胞肥大和钙处理（Col1a2、Nppa和Serca2）。随后的相关分析允许在梗死组织中识别共享可比转录调节模式的新因素。这些已知标记基因的表达水平与协同调节基因的表达之间的强相关性可以在人类缺血心脏组织样本中得到证实。后续分析发现SOX9是大部分纤维化相关基因的共同转录调节因子，这些基因在缺血性损伤条件下被激活。谱系追踪实验表明，大多数col1阳性的成纤维细胞源于表达Sox9的细胞池，体内Sox9的缺失减弱了缺血损伤时心脏纤维化的反应。SOX9和COL1的共定位也可在缺血性心脏病患者中得到证实。结论：基于精确的局部表达线索，tomo-seq可以揭示参与心脏重塑特定方面的新基因和关键转录因子。使用tomo-seq，我们能够揭示SOX9作为心脏纤维化关键调节因子的未知相关性，指出SOX9是心脏纤维化的潜在治疗靶点。
BACKGROUND: Cardiac ischemic injury induces a pathological remodeling response, which can ultimately lead to heart failure. Detailed mechanistic insights into molecular signaling pathways relevant for different aspects of cardiac remodeling will support the identification of novel therapeutic targets.METHODS: Although genome-wide transcriptome analysis on diseased tissues has greatly advanced our understanding of the regulatory networks that drive pathological changes in the heart, this approach has been disadvantaged by the fact that the signals are derived from tissue homogenates. Here we used tomo-seq to obtain a genome-wide gene expression signature with high spatial resolution spanning from the infarcted area to the remote to identify new regulators of cardiac remodeling. Cardiac tissue samples from patients suffering from ischemic heart disease were used to validate our findings.RESULTS: Tracing transcriptional differences with a high spatial resolution across the infarcted heart enabled us to identify gene clusters that share a comparable expression profile. The spatial distribution patterns indicated a separation of expressional changes for genes involved in specific aspects of cardiac remodeling, such as fibrosis, cardiomyocyte hypertrophy, and calcium handling (Col1a2, Nppa, and Serca2). Subsequent correlation analysis allowed for the identification of novel factors that share a comparable transcriptional regulation pattern across the infarcted tissue. The strong correlation between the expression levels of these known marker genes and the expression of the coregulated genes could be confirmed in human ischemic cardiac tissue samples. Follow-up analysis identified SOX9 as common transcriptional regulator of a large portion of the fibrosis-related genes that become activated under conditions of ischemic injury. Lineage-tracing experiments indicated that the majority of COL1-positive fibroblasts stem from a pool of SOX9-expressing cells, and in vivo loss of Sox9 blunted the cardiac fibrotic response on ischemic injury. The colocalization between SOX9 and COL1 could also be confirmed in patients suffering from ischemic heart disease.CONCLUSIONS: Based on the exact local expression cues, tomo-seq can serve to reveal novel genes and key transcription factors involved in specific aspects of cardiac remodeling. Using tomo-seq, we were able to unveil the unknown relevance of SOX9 as a key regulator of cardiac fibrosis, pointing to SOX9 as a potential therapeutic target for cardiac fibrosis.