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A CRISPR Screen Identifies Myc-associated Zinc Finger Protein (MAZ) as an Insulator Functioning at CTCF boundaries in Hox Clusters

View ORCID ProfileHavva Ortabozkoyun-Kara, View ORCID ProfilePin-Yao Huang, View ORCID ProfileHyunwoo Cho, Varun Narendra, View ORCID ProfileGary Leroy, View ORCID ProfileJane A. Skok, Aristotelis Tsirigos, View ORCID ProfileEsteban O. Mazzoni, View ORCID ProfileDanny Reinberg
doi: https://doi.org/10.1101/2020.08.25.267237
Havva Ortabozkoyun-Kara
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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  • ORCID record for Havva Ortabozkoyun-Kara
Pin-Yao Huang
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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Hyunwoo Cho
3Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
4Applied Bioinformatics Laboratories, New York University School of Medicine, New York, NY, USA
5Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA
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Varun Narendra
6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Gary Leroy
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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Jane A. Skok
3Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
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  • ORCID record for Jane A. Skok
Aristotelis Tsirigos
3Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
4Applied Bioinformatics Laboratories, New York University School of Medicine, New York, NY, USA
7Institute for Computational Medicine, NYU School of Medicine, New York, NY 10016
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Esteban O. Mazzoni
8Department of Biology, New York University, New York, NY 10003, USA
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  • ORCID record for Esteban O. Mazzoni
Danny Reinberg
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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  • For correspondence: Danny.Reinberg@nyulangone.org
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Abstract

The essential CCCTC-binding factor (CTCF) is critical to three-dimensional (3D) genome organization. CTCF binding insulates active and repressed genes within the Hox clusters upon differentiation, but such binding does not participate in boundary formation in all cell types, such as embryonic stem cells. We conducted a genome-wide CRISPR knockout screen to identify genes required for CTCF boundary activity at the HoxA cluster, complemented by novel biochemical approaches. This screen identified Myc-associated zinc finger protein (MAZ) as a CTCF insulator co-factor, among other candidates listed herein. MAZ depletion or specific deletion of MAZ motifs within the Hox clusters led to de-repression of posterior Hox genes immediately after CTCF boundaries upon differentiation, which phenocopied deletion of the proximal CTCF motifs. Similar to CTCF, MAZ interacted with the cohesin subunit, RAD21. Upon loss of MAZ, local contacts within topologically associated domains (TADs) were disrupted, as evidenced by HiC analysis. Thus, MAZ is a novel factor sharing insulation properties with CTCF and contributing to the genomic architectural organization.

One Sentence Summary MAZ is identified as an insulator functioning at CTCF boundaries delimiting active and repressed genes at Hox clusters

Competing Interest Statement

D.R. was a cofounder of Constellation Pharmaceuticals and Fulcrum Therapeutics. Currently, D.R has no affiliation with either company. The authors declare that they have no other competing interests.

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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Posted August 26, 2020.
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A CRISPR Screen Identifies Myc-associated Zinc Finger Protein (MAZ) as an Insulator Functioning at CTCF boundaries in Hox Clusters
Havva Ortabozkoyun-Kara, Pin-Yao Huang, Hyunwoo Cho, Varun Narendra, Gary Leroy, Jane A. Skok, Aristotelis Tsirigos, Esteban O. Mazzoni, Danny Reinberg
bioRxiv 2020.08.25.267237; doi: https://doi.org/10.1101/2020.08.25.267237
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A CRISPR Screen Identifies Myc-associated Zinc Finger Protein (MAZ) as an Insulator Functioning at CTCF boundaries in Hox Clusters
Havva Ortabozkoyun-Kara, Pin-Yao Huang, Hyunwoo Cho, Varun Narendra, Gary Leroy, Jane A. Skok, Aristotelis Tsirigos, Esteban O. Mazzoni, Danny Reinberg
bioRxiv 2020.08.25.267237; doi: https://doi.org/10.1101/2020.08.25.267237

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