Resolving the 3D Landscape of Transcription-Linked Mammalian Chromatin Folding

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

doi:10.1016/j.molcel.2020.03.002

Resolving the 3D Landscape of Transcription-Linked Mammalian Chromatin Folding

Mol Cell. 2020 May 7;78(3):539-553.e8. doi: 10.1016/j.molcel.2020.03.002. Epub 2020 Mar 25.

Authors

Tsung-Han S Hsieh¹, Claudia Cattoglio², Elena Slobodyanyuk², Anders S Hansen³, Oliver J Rando⁴, Robert Tjian⁵, Xavier Darzacq⁶

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Li Ka Shing Center for Biomedical and Health Sciences, University of California, Berkeley, Berkeley, CA 94720, USA; CIRM Center of Excellence, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
² Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Li Ka Shing Center for Biomedical and Health Sciences, University of California, Berkeley, Berkeley, CA 94720, USA; CIRM Center of Excellence, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Li Ka Shing Center for Biomedical and Health Sciences, University of California, Berkeley, Berkeley, CA 94720, USA; CIRM Center of Excellence, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁴ Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁵ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Li Ka Shing Center for Biomedical and Health Sciences, University of California, Berkeley, Berkeley, CA 94720, USA; CIRM Center of Excellence, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: jmlim@berkeley.edu.
⁶ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Li Ka Shing Center for Biomedical and Health Sciences, University of California, Berkeley, Berkeley, CA 94720, USA; CIRM Center of Excellence, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: darzacq@berkeley.edu.

Abstract

Whereas folding of genomes at the large scale of epigenomic compartments and topologically associating domains (TADs) is now relatively well understood, how chromatin is folded at finer scales remains largely unexplored in mammals. Here, we overcome some limitations of conventional 3C-based methods by using high-resolution 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 segregates TAD regions into various finer-scale structures with distinct regulatory features including stripes, dots, and domains linking promoters-to-promoters (P-P) or enhancers-to-promoters (E-P) and bundle contacts between Polycomb regions. E-P stripes extending from the edge of domains predominantly link co-expressed loci, often in the absence of CTCF and cohesin occupancy. Acute inhibition of transcription disrupts these gene-related folding features without altering higher-order chromatin structures. Our study uncovers previously obscured finer-scale genome organization, establishing functional links between chromatin folding and gene regulation.

Keywords: 30 nm chromatin fiber; 3D genome; CTCF; Micro-C; Pol II; TAD; enhancer-promoter (E-P) interactions; loop extrusion; transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
CCCTC-Binding Factor / genetics
Chromatin / chemistry*
Chromatin / genetics
Chromatin / metabolism*
Chromatin Assembly and Disassembly / genetics*
DNA Polymerase II / genetics
DNA Polymerase II / metabolism
Embryonic Stem Cells / physiology
Enhancer Elements, Genetic
Gene Expression Regulation
Genome Components
Mice
Promoter Regions, Genetic
Transcription Factors / genetics
Transcription Factors / metabolism
Transcription, Genetic*

Substances

CCCTC-Binding Factor
Chromatin
Ctcf protein, mouse
Transcription Factors
DNA Polymerase II

Abstract

Publication types

MeSH terms

Substances

Grants and funding