1. Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment
- Author
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Ranjan Sen, Yuhua Sun, William Wagstaff, Todd C. McDevitt, Changying Guo, Michael E.G. Sauria, James Taylor, Michael Bland, Joshua S.K. Bell, Tracy A. Hookway, Tatiana I. Gerasimova, Bryan R. Lajoie, Job Dekker, Victor G. Corces, Stephen Dalton, Jennifer E. Phillips-Cremins, Chin-Tong Ong, and Amartya Sanyal
- Subjects
CCCTC-Binding Factor ,Chromosomal Proteins, Non-Histone ,Cell Cycle Proteins ,Biology ,Genome ,General Biochemistry, Genetics and Molecular Biology ,Chromosome conformation capture ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Neural Stem Cells ,Animals ,Cell Lineage ,Promoter Regions, Genetic ,Embryonic Stem Cells ,030304 developmental biology ,Genetics ,0303 health sciences ,Mediator Complex ,Cohesin ,Biochemistry, Genetics and Molecular Biology(all) ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,Epigenome ,Sequence Analysis, DNA ,Embryonic stem cell ,Chromatin ,Repressor Proteins ,Enhancer Elements, Genetic ,CTCF ,Evolutionary biology ,Gene Knockdown Techniques ,Chromatin Loop ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
SummaryUnderstanding the topological configurations of chromatin may reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here, we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3D interactions that undergo marked reorganization at the submegabase scale during differentiation. Distinct combinations of CCCTC-binding factor (CTCF), Mediator, and cohesin show widespread enrichment in chromatin interactions at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant subdomains. Conversely, Mediator/cohesin bridge short-range enhancer-promoter interactions within and between larger subdomains. Knockdown of Smc1 or Med12 in embryonic stem cells results in disruption of spatial architecture and downregulation of genes found in cohesin-mediated interactions. We conclude that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales.
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