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CTCF Promotes Long-range Enhancer-promoter Interactions and Lineage-specific Gene Expression in Mammalian Cells

Naoki Kubo, Haruhiko Ishii, Xiong Xiong, Simona Bianco, Franz Meitinger, Rong Hu, James D. Hocker, Mattia Conte, David Gorkin, Miao Yu, Bin Li, Jesse R. Dixon, Ming Hu, View ORCID ProfileMario Nicodemi, Huimin Zhao, View ORCID ProfileBing Ren
doi: https://doi.org/10.1101/2020.03.21.001693
Naoki Kubo
1Ludwig Institute for Cancer Research, La Jolla, CA, USA
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Haruhiko Ishii
1Ludwig Institute for Cancer Research, La Jolla, CA, USA
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Xiong Xiong
2Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
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Simona Bianco
3Department of Physics, University of Naples Federico II, and INFN Complesso di Monte Sant’Angelo, Naples, Italy
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Franz Meitinger
1Ludwig Institute for Cancer Research, La Jolla, CA, USA
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Rong Hu
1Ludwig Institute for Cancer Research, La Jolla, CA, USA
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James D. Hocker
1Ludwig Institute for Cancer Research, La Jolla, CA, USA
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Mattia Conte
3Department of Physics, University of Naples Federico II, and INFN Complesso di Monte Sant’Angelo, Naples, Italy
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David Gorkin
4Department of Cellular and Molecular Medicine, Center for Epigenomics, University of California San Diego School of Medicine, La Jolla, CA, USA
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Miao Yu
1Ludwig Institute for Cancer Research, La Jolla, CA, USA
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Bin Li
1Ludwig Institute for Cancer Research, La Jolla, CA, USA
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Jesse R. Dixon
5Salk Institute for Biological Studies, La Jolla, CA, USA
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Ming Hu
6Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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Mario Nicodemi
3Department of Physics, University of Naples Federico II, and INFN Complesso di Monte Sant’Angelo, Naples, Italy
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  • ORCID record for Mario Nicodemi
Huimin Zhao
2Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
7Departments of Chemistry, Biochemistry, and Bioengineering, and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
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Bing Ren
1Ludwig Institute for Cancer Research, La Jolla, CA, USA
4Department of Cellular and Molecular Medicine, Center for Epigenomics, University of California San Diego School of Medicine, La Jolla, CA, USA
8Department of Cellular and Molecular Medicine, Moores Cancer Center and Institute of Genome Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
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  • ORCID record for Bing Ren
  • For correspondence: biren@ucsd.edu
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Abstract

Topologically associating domains (TAD) and insulated neighborhoods (INs) have been proposed to constrain enhancer-promoter communications to enable cell-type specific transcription programs, but recent studies show that disruption of TADs and INs resulted in relatively mild changes in gene expression profiles. To better understand the role of chromatin architecture in dynamic enhancer-promoter contacts and lineage-specific gene expression, we have utilized the auxin-inducible degron system to acutely deplete CTCF, a key factor involved in TADs and IN formation, in mouse embryonic stem cells (mESCs) and examined chromatin architecture and gene regulation during neural differentiation. We find that while CTCF depletion leads to global weakening of TAD boundaries and loss of INs, only a minor fraction of enhancer-promoter contacts are lost, affecting a small subset of genes. The CTCF-dependent enhancer-promoter contacts tend to be long-range, spanning hundreds of kilobases, and are established directly by CTCF binding to promoters. Disruption of CTCF binding at the promoter reduces enhancer-promoter contacts and transcription, while artificial tethering of CTCF to the promoter restores the enhancer-promoter contacts and gene activation. Genome-wide analysis of CTCF binding and gene expression across multiple mouse tissues suggests that CTCF-dependent promoter-enhancer contacts may regulate expression of additional mouse genes, particularly those expressed in the brain. Our results uncover both CTCF-dependent and independent enhancer-promoter contacts, and highlight a distinct role for CTCF in promoting enhancer-promoter contacts and gene activation in addition to its insulator function.

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Posted March 23, 2020.
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CTCF Promotes Long-range Enhancer-promoter Interactions and Lineage-specific Gene Expression in Mammalian Cells
Naoki Kubo, Haruhiko Ishii, Xiong Xiong, Simona Bianco, Franz Meitinger, Rong Hu, James D. Hocker, Mattia Conte, David Gorkin, Miao Yu, Bin Li, Jesse R. Dixon, Ming Hu, Mario Nicodemi, Huimin Zhao, Bing Ren
bioRxiv 2020.03.21.001693; doi: https://doi.org/10.1101/2020.03.21.001693
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CTCF Promotes Long-range Enhancer-promoter Interactions and Lineage-specific Gene Expression in Mammalian Cells
Naoki Kubo, Haruhiko Ishii, Xiong Xiong, Simona Bianco, Franz Meitinger, Rong Hu, James D. Hocker, Mattia Conte, David Gorkin, Miao Yu, Bin Li, Jesse R. Dixon, Ming Hu, Mario Nicodemi, Huimin Zhao, Bing Ren
bioRxiv 2020.03.21.001693; doi: https://doi.org/10.1101/2020.03.21.001693

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