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CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains

Hui Huang, Quan Zhu, Adam Jussila, Yuanyuan Han, Bogdan Bintu, Colin Kern, Mattia Conte, Yanxiao Zhang, Simona Bianco, Andrea Chiariello, Miao Yu, Rong Hu, Ivan Juric, Ming Hu, Mario Nicodemi, Xiaowei Zhuang, View ORCID ProfileBing Ren
doi: https://doi.org/10.1101/2020.07.07.192526
Hui Huang
1Ludwig Institute for Cancer Research, La Jolla, California 92093, USA
2University of California, San Diego, Biomedical Sciences Graduate Program, La Jolla, California 92093, USA
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Quan Zhu
3University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Center for Epigenomics, 9500 Gilman Drive, La Jolla, CA 92093-0653, USA
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Adam Jussila
1Ludwig Institute for Cancer Research, La Jolla, California 92093, USA
4Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA 92093, USA
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Yuanyuan Han
3University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Center for Epigenomics, 9500 Gilman Drive, La Jolla, CA 92093-0653, USA
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Bogdan Bintu
5Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, Cambridge, MA 02138, USA
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Colin Kern
3University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Center for Epigenomics, 9500 Gilman Drive, La Jolla, CA 92093-0653, USA
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Mattia Conte
6Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso di Monte Sant’Angelo, Naples, Italy
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Yanxiao Zhang
1Ludwig Institute for Cancer Research, La Jolla, California 92093, USA
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Simona Bianco
6Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso di Monte Sant’Angelo, Naples, Italy
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Andrea Chiariello
6Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso di Monte Sant’Angelo, Naples, Italy
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Miao Yu
1Ludwig Institute for Cancer Research, La Jolla, California 92093, USA
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Rong Hu
1Ludwig Institute for Cancer Research, La Jolla, California 92093, USA
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Ivan Juric
7Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
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Ming Hu
7Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
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Mario Nicodemi
6Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso di Monte Sant’Angelo, Naples, Italy
8Berlin Institute for Medical Systems Biology, Max Delbrück Centre (MDC) for Molecular Medicine, Berlin, Germany
9Berlin Institute of Health (BIH), Berlin, Germany
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Xiaowei Zhuang
5Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, Cambridge, MA 02138, USA
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Bing Ren
1Ludwig Institute for Cancer Research, La Jolla, California 92093, USA
3University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Center for Epigenomics, 9500 Gilman Drive, La Jolla, CA 92093-0653, USA
10University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, and Moores Cancer Center, 9500 Gilman Drive, La Jolla, CA 92093-0653, USA
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  • ORCID record for Bing Ren
  • For correspondence: biren@health.ucsd.edu
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Abstract

Insulators play a critical role in spatiotemporal gene expression in metazoans by separating active and repressive chromatin domains and preventing inappropriate enhancer-promoter contacts. The evolutionarily conserved CCCTC-binding factor (CTCF) is required for insulator function in mammals, but not all of its binding sites act as insulators. Here, we explore the sequence requirements of CTCF-mediated transcriptional insulation with the use of a sensitive insulator reporter assay in mouse embryonic stem cells. We find that insulation potency depends on the number of CTCF binding sites in tandem. Furthermore, CTCF-mediated insulation is dependent on DNA sequences flanking its core binding motifs, and CTCF binding sites at topologically associating domain(TAD) boundaries are more likely to function as insulators than those outside TAD boundaries, independent of binding strength. Using chromosomal conformation capture assays and high-resolution chromatin imaging techniques, we demonstrate that insulators form local chromatin domain boundaries and reduce enhancer-promoter contacts. Taken together, our results provide strong genetic, molecular, and structural evidence connecting chromatin topology to the action of insulators in the mammalian genome.

Competing Interest Statement

Bing Ren is a co-founder and consultant for Arima Genomics, Inc. Xiaowei Zhuang is a co-founder and consultant for Vizgen, Inc.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153400

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains
Hui Huang, Quan Zhu, Adam Jussila, Yuanyuan Han, Bogdan Bintu, Colin Kern, Mattia Conte, Yanxiao Zhang, Simona Bianco, Andrea Chiariello, Miao Yu, Rong Hu, Ivan Juric, Ming Hu, Mario Nicodemi, Xiaowei Zhuang, Bing Ren
bioRxiv 2020.07.07.192526; doi: https://doi.org/10.1101/2020.07.07.192526
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CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains
Hui Huang, Quan Zhu, Adam Jussila, Yuanyuan Han, Bogdan Bintu, Colin Kern, Mattia Conte, Yanxiao Zhang, Simona Bianco, Andrea Chiariello, Miao Yu, Rong Hu, Ivan Juric, Ming Hu, Mario Nicodemi, Xiaowei Zhuang, Bing Ren
bioRxiv 2020.07.07.192526; doi: https://doi.org/10.1101/2020.07.07.192526

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