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

• Published in: Circulation (New York, N.Y.) N.Y.), 2019-04, Vol.139 (16), p.1937-1956
• Main Authors: Lee, Dominic Paul, Tan, Wilson Lek Wen, Anene-Nzelu, Chukwuemeka George, Lee, Chang Jie Mick, Li, Peter Yiqing, Luu, Tuan Danh Anh, Chan, Cheryl Xueli, Tiang, Zenia, Ng, Shi Ling, Huang, Xingfan, Efthymios, Motakis, Autio, Matias I, Jiang, Jianming, Fullwood, Melissa Jane, Prabhakar, Shyam, Lieberman Aiden, Erez, Foo, Roger Sik-Yin
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Aortic Valve Stenosis - genetics; CCCTC-Binding Factor - genetics; CCCTC-Binding Factor - metabolism; Cells, Cultured; Chromatin - metabolism; Chromatin Assembly and Disassembly; Disease Models, Animal; Epigenesis, Genetic; Gene Expression Regulation; Gene Ontology; Gene Regulatory Networks; Heart Failure - genetics; Histones - metabolism; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac - physiology; Stress, Physiological
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.118.036726

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 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.