Robust CTCF-Based Chromatin Architecture Underpins Epigenetic Changes in the Heart Failure Stress-Gene Response
Robust CTCF-Based Chromatin Architecture Underpins Epigenetic Changes in the Heart Failure Stress-Gene Response
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DOI：
10.1161/circulationaha.118.036726
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发表时间：
2019-04-16
期刊：
影响因子：
37.8
通讯作者：
Foo, Roger Sik-Yin
中科院分区：
文献类型：
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作者：
Lee, Dominic Paul;Tan, Wilson Lek Wen;Foo, Roger Sik-Yin
背景技术背景：人类基因组在3维中折叠，在细胞核内形成数千个染色质环，包裹基因和顺式调控元件，用于精确的基因表达控制。环的物理系链由DNA结合蛋白CTCF和粘附素环复合物锚定。由于心力衰竭的特征是标志性基因表达的变化，最近有报道说，大量的CTCF相关的染色质重组支持心肌应激基因反应，在CTCF敲除中观察到染色质结构域边界的变化。我们进行了一个独立的和正交分析染色质组织与小鼠压力超负荷模型的心肌应力（横向主动脉缩窄）和心肌细胞特异性敲除Ctcf。我们还下载了发表的数据集类似的心脏小鼠模型，并进行独立reanalysis.RESULTS：我们发现，心肌细胞染色质结构保持广泛稳定的横向主动脉缩窄心脏，而Ctcf基因敲除导致约99%的全球染色质循环取消。疾病基因表达的变化，而不是相关的差异组蛋白H3 K27-乙酰化富集在其各自的近端和远端相互作用的基因组增强子限制在这些静态染色质结构。此外，共调节基因被映射出作为互连的基因集的基础上，他们的多基因3D interactions.CONCLUSIONS：这项工作揭示了一个更稳定的全基因组染色质框架比以前描述的。心肌应激基因转录通过H3 K27-乙酰化增强子富集动力学和共调节基因网络来响应。稳健和完整的CTCF循环是诱导快速和准确的应激反应所必需的。
BACKGROUND: The human genome folds in 3 dimensions to form thousands of chromatin loops inside the nucleus, encasing genes and cis-regulatory elements for accurate gene expression control. Physical tethers of loops are anchored by the DNA-binding protein CTCF and the cohesin ring complex. Because heart failure is characterized by hallmark gene expression changes, it was recently reported that substantial CTCF-related chromatin reorganization underpins the myocardial stress-gene response, paralleled by chromatin domain boundary changes observed in CTCF knockout.METHODS: We undertook an independent and orthogonal analysis of chromatin organization with mouse pressure-overload model of myocardial stress (transverse aortic constriction) and cardiomyocyte-specific knockout of Ctcf. We also downloaded published data sets of similar cardiac mouse models and subjected them to independent reanalysis.RESULTS: We found that the cardiomyocyte chromatin architecture remains broadly stable in transverse aortic constriction hearts, whereas Ctcf knockout resulted in approximate to 99% abolition of global chromatin loops. Disease gene expression changes correlated instead with differential histone H3K27-acetylation enrichment at their respective proximal and distal interacting genomic enhancers confined within these static chromatin structures. Moreover, coregulated genes were mapped out as interconnected gene sets on the basis of their multigene 3D interactions.CONCLUSIONS: This work reveals a more stable genome-wide chromatin framework than previously described. Myocardial stress-gene transcription responds instead through H3K27-acetylation enhancer enrichment dynamics and gene networks of coregulation. Robust and intact CTCF looping is required for the induction of a rapid and accurate stress response.