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

Autor:	Bansal K; Department of Immunology, Harvard Medical School, Boston, MA 02115.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.; Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, India., Michelson DA; Department of Immunology, Harvard Medical School, Boston, MA 02115.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115., Ramirez RN; Department of Immunology, Harvard Medical School, Boston, MA 02115.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115., Viny AD; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065.; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Levine RL; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065.; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Benoist C; Department of Immunology, Harvard Medical School, Boston, MA 02115; cbdm@hms.harvard.edu.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115., Mathis D; Department of Immunology, Harvard Medical School, Boston, MA 02115; cbdm@hms.harvard.edu.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Sep 21; Vol. 118 (38).
DOI:	10.1073/pnas.2110991118
Abstrakt:	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. Competing Interests: Competing interest statement: R.L.L. is on the supervisory board of Qiagen, and the scientific advisory boards of Loxo, Imago, Mana, Auron, C4 Therapeutics, and IsoPlexis, which include equity interest; receives research support from and consulted for Celgene and Roche, and consults for Incyte, Lilly, Janssen, Astellas, MorphoSys, and Novartis; receives research support from Prelude; and has received honoraria from Astra Zeneca, Roche, Lilly, and Amgen for invited lectures and from Gilead for grant reviews.
Databáze:	MEDLINE
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