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Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic CellsNovelty and Significance
Circulation Research ( IF 20.1 ) Pub Date : 2017-11-10 , DOI: 10.1161/circresaha.117.311367
Ming-Tao Zhao 1 , Ning-Yi Shao 1 , Shijun Hu 1 , Ning Ma 1 , Rajini Srinivasan 1 , Fereshteh Jahanbani 1 , Jaecheol Lee 1 , Sophia L. Zhang 1 , Michael P. Snyder 1 , Joseph C. Wu 1
Affiliation  

Rationale: Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression during embryonic heart development and somatic cell reprogramming. It is not well known how chromatin marks in regulatory DNA elements are modulated to establish cell type–specific gene expression in the human heart.
Objective: We aimed to decipher the cell type–specific epigenetic signatures in regulatory DNA elements and how they modulate heart-specific gene expression.
Methods and Results: We profiled genome-wide transcriptional activity and a variety of epigenetic marks in the regulatory DNA elements using massive RNA-seq (n=12) and ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing; n=84) in human endothelial cells (CD31+CD144+), cardiac progenitor cells (Sca-1+), fibroblasts (DDR2+), and their respective induced pluripotent stem cells. We uncovered 2 classes of regulatory DNA elements: class I was identified with ubiquitous enhancer (H3K4me1) and promoter (H3K4me3) marks in all cell types, whereas class II was enriched with H3K4me1 and H3K4me3 in a cell type–specific manner. Both class I and class II regulatory elements exhibited stimulatory roles in nearby gene expression in a given cell type. However, class I promoters displayed more dominant regulatory effects on transcriptional abundance regardless of distal enhancers. Transcription factor network analysis indicated that human induced pluripotent stem cells and somatic cells from the heart selected their preferential regulatory elements to maintain cell type–specific gene expression. In addition, we validated the function of these enhancer elements in transgenic mouse embryos and human cells and identified a few enhancers that could possibly regulate the cardiac-specific gene expression.
Conclusions: Given that a large number of genetic variants associated with human diseases are located in regulatory DNA elements, our study provides valuable resources for deciphering the epigenetic modulation of regulatory DNA elements that fine-tune spatiotemporal gene expression in human cardiac development and diseases.


中文翻译:

细胞类型特定的染色质签名强调人类诱导的多能干细胞和体细胞新颖性和意义的监管DNA元素。

原理:人类基因组中的调节性DNA元素在确定胚胎心脏发育和体细胞重编程过程中的转录丰度和时空基因表达方面起着重要作用。尚不知道如何调节调节性DNA元件中的染色质标记以在人的心脏中建立特定于细胞类型的基因表达。
目的:我们旨在破译调节性DNA元件中特定于细胞类型的表观遗传学特征,以及它们如何调节心脏特异性基因的表达。
方法和结果:我们使用大规模RNA-seq(n = 12)和ChIP-seq(染色质免疫沉淀与高通量测序; n = 84)对基因组范围的转录活性和调节性DNA元件中的多种表观遗传标记进行了分析。人内皮细胞(CD31 + CD144 +),心脏祖细胞(Sca-1 +),成纤维细胞(DDR2 +),以及它们各自诱导的多能干细胞。我们发现了2类调控DNA元素:在所有细胞类型中,I类均被普遍存在的增强子(H3K4me1)和启动子(H3K4me3)标记所识别,而II类则以特定于细胞类型的方式富含H3K4me1和H3K4me3。在给定的细胞类型中,I类和II类调节元件均在附近基因表达中表现出刺激作用。但是,无论远端增强子如何,I类启动子在转录丰度上显示出更多的主要调节作用。转录因子网络分析表明,人心脏诱导的多能干细胞和体细胞选择了它们的优先调控元件来维持特定于细胞类型的基因表达。此外,
结论:鉴于与人类疾病相关的大量遗传变异位于调控DNA元件中,我们的研究为破译调控DNA的表观遗传学调制提供了宝贵的资源,这些调控DNA元素可微调人的心脏发育和疾病中的时空基因表达。
更新日期:2017-11-09
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