Robust CTCF-Based Chromatin Architecture Underpins Epigenetic Changes in the Heart Failure Stress–Gene Response

作者：Dominic Paul Lee, Wilson Lek Wen Tan, Chukwuemeka George Anene-Nzelu, Chang Jie Mick Lee, Peter Yiqing Li, Tuan Danh Anh Luu, Cheryl Xueli Chan, Zenia Tiang, Shi Ling Ng, Xingfan Huang, Efthymios Motakis, Matias Autio, Jianming Jiang, Melissa J. Fullwood, Shyam Prabhakar, Erez Lieberman Aiden, Roger Foo · 发表于：Circulation · 年份：2019 · DOI：10.1161/circulationaha.118.036726 · 被引用次数：56 · 研究领域：Genomics and Chromatin Dynamics、Chromatin Remodeling and Cancer、Congenital heart defects research

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 ≈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 sta...