Robust CTCF-Based Chromatin Architecture Underpins Epigenetic Changes in the Heart Failure Stress–Gene Response
| Autor: | Roger Foo, Cheryl Xueli Chan, Dominic Paul Lee, Xingfan Huang, Chang Jie Mick Lee, Sarah Ng, Melissa J. Fullwood, Motakis Efthymios, Erez Lieberman Aiden, Zenia Tiang, Shyam Prabhakar, Wen Tan Wl, Chukwuemeka George Anene-Nzelu, Matias I. Autio, Tuan Danh Anh Luu, Jianming Jiang, Peter Yiqing Li |
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| Rok vydání: | 2019 |
| Předmět: |
CCCTC-Binding Factor
Computational biology 030204 cardiovascular system & hematology Epigenesis Genetic Histones Mice 03 medical and health sciences 0302 clinical medicine Stress Physiological Physiology (medical) Gene expression Animals Humans Medicine Gene Regulatory Networks Myocytes Cardiac Epigenetics Gene Cells Cultured 030304 developmental biology Epigenomics Heart Failure Mice Knockout 0303 health sciences business.industry Acetylation Aortic Valve Stenosis Chromatin Assembly and Disassembly Chromatin Mice Inbred C57BL Disease Models Animal Gene Ontology medicine.anatomical_structure Gene Expression Regulation CTCF Human genome Cardiology and Cardiovascular Medicine business Nucleus |
| Zdroj: | Circulation. 139:1937-1956 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.118.036726 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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