Dominic Paul Lee1,2, Wilson Lek Wen Tan1,2, Chukwuemeka George Anene-Nzelu1,2, Chang Jie Mick Lee1,2, Peter Yiqing Li2, Tuan Danh Anh Luu2, Cheryl Xueli Chan1,2, Zenia Tiang1,2, Shi Ling Ng1,2, Xingfan Huang3,4, Motakis Efthymios1,2, Matias I Autio1,2, Jianming Jiang2,5, Melissa Jane Fullwood6,7, Shyam Prabhakar1, Erez Lieberman Aiden3,4, Roger Sik-Yin Foo1,2. 1. Genome Institute of Singapore (D.P.L., W.L.W.T., C.G.A.-N., C.J.M.L., C.X.C., Z.T., S.L.N., M.E., M.I.A., S.P., R.S.-Y.F.). 2. Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, Singapore (D.P.L., W.L.W.T., C.G.A.-N., C.J.M.L., P.Y.L., T.L.D.A., C.X.C., Z.T., S.L.N., M.E., M.I.A., J.J., R.S.-Y.F.). 3. Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX (X.H., E.L.A.). 4. Center for Theoretical Biological Physics and Department of Computer Science, Rice University, Houston, TX (X.H., E.L.A.). 5. Department of Biochemistry, School of Medicine (J.J.), National University of Singapore. 6. Cancer Science Institute (M.J.F.), National University of Singapore. 7. School of Biological Sciences, Nanyang Technological University, Singapore (M.J.F.).
Abstract
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.
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.
Authors: Roger Sik-Yin Foo; Chukwuemeka George Anene-Nzelu; Manuel Rosa-Garrido; Thomas M Vondriska Journal: Circulation Date: 2019-08-05 Impact factor: 29.690
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Authors: Chukwuemeka G Anene-Nzelu; Mick C J Lee; Wilson L W Tan; Albert Dashi; Roger S Y Foo Journal: Nat Rev Cardiol Date: 2021-08-11 Impact factor: 32.419