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Aire regulates chromatin looping by evicting CTCF from domain boundaries and favoring accumulation of cohesin on superenhancers.

Authors
  • Bansal, Kushagra1, 2, 3
  • Michelson, Daniel A1, 2
  • Ramirez, Ricardo N1, 2
  • Viny, Aaron D4, 5, 6, 7
  • Levine, Ross L4, 5, 6, 7
  • Benoist, Christophe8, 2
  • Mathis, Diane8, 2
  • 1 Department of Immunology, Harvard Medical School, Boston, MA 02115.
  • 2 Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
  • 3 Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, India. , (India)
  • 4 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 5 Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065. , (Mali)
  • 6 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 7 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 8 Department of Immunology, Harvard Medical School, Boston, MA 02115; [email protected]
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Sep 21, 2021
Volume
118
Issue
38
Identifiers
DOI: 10.1073/pnas.2110991118
PMID: 34518235
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Aire controls immunological tolerance by driving promiscuous expression of a large swath of the genome in medullary thymic epithelial cells (mTECs). Its molecular mechanism remains enigmatic. High-resolution chromosome-conformation capture (Hi-C) experiments on ex vivo mTECs revealed Aire to have a widespread impact on higher-order chromatin structure, disfavoring architectural loops while favoring transcriptional loops. In the presence of Aire, cohesin complexes concentrated on superenhancers together with mediator complexes, while the CCCTC-binding factor (CTCF) was relatively depleted from structural domain boundaries. In particular, Aire associated with the cohesin loader, NIPBL, strengthening this factor's affiliation with cohesin's enzymatic subunits. mTEC transcripts up-regulated in the presence of Aire corresponded closely to those down-regulated in the absence of one of the cohesin subunits, SA-2. A mechanistic model incorporating these findings explains many of the unusual features of Aire's impact on mTEC transcription, providing molecular insight into tolerance induction.

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