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Resolving the 3D landscape of transcription-linked mammalian chromatin folding

By Tsung-Han S. Hsieh, Elena Slobodyanyuk, Anders S. Hansen, Claudia Cattoglio, Oliver J. Rando, Robert Tjian, Xavier Darzacq

Posted 17 May 2019
bioRxiv DOI: 10.1101/638775 (published DOI: 10.1016/j.molcel.2020.03.002)

Chromatin folding below the scale of topologically associating domains (TADs) remains largely unexplored in mammals. Here, we used a high-resolution 3C-based method, Micro-C, to probe links between 3D-genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregate TAD regions into "microTADs" with distinct regulatory features. Enhancer-promoter and promoter-promoter interactions extending from the edge of these domains predominantly link co-regulated loci, often independently of CTCF/Cohesin. Acute inhibition of transcription disrupts the gene-related folding features without altering higher-order chromatin structures. Intriguingly, we detect "two-start" zig-zag 30-nanometer chromatin fibers. Our work uncovers the finer-scale genome organization that establishes novel functional links between chromatin folding and gene regulation.

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