Polymerization of ZBTB transcription factors regulates chromatin occupancy.

Autor:	Park PMC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Park J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Brown J; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Hunkeler M; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Roy Burman SS; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Donovan KA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Yoon H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Nowak RP; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Słabicki M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Ebert BL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA. Electronic address: benjamin_ebert@dfci.harvard.edu., Fischer ES; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: eric_fischer@dfci.harvard.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Jul 11; Vol. 84 (13), pp. 2511-2524.e8.
DOI:	10.1016/j.molcel.2024.06.010
Abstrakt:	BCL6, an oncogenic transcription factor (TF), forms polymers in the presence of a small-molecule molecular glue that stabilizes a complementary interface between homodimers of BCL6's broad-complex, tramtrack, and bric-à-brac (BTB) domain. The BTB domains of other proteins, including a large class of TFs, have similar architectures and symmetries, raising the possibility that additional BTB proteins self-assemble into higher-order structures. Here, we surveyed 189 human BTB proteins with a cellular fluorescent reporter assay and identified 18 ZBTB TFs that show evidence of polymerization. Through biochemical and cryoelectron microscopy (cryo-EM) studies, we demonstrate that these ZBTB TFs polymerize into filaments. We found that BTB-domain-mediated polymerization of ZBTB TFs enhances chromatin occupancy within regions containing homotypic clusters of TF binding sites, leading to repression of target genes. Our results reveal a role of higher-order structures in regulating ZBTB TFs and suggest an underappreciated role for TF polymerization in modulating gene expression. Competing Interests: Declaration of interests M.S. and B.L.E. have received research funding from Calico Life Sciences LLC. K.A.D. is a consultant to Kronos Bio and Neomorph Inc. B.L.E. has received research funding from Novartis, has received consulting fees from Abbvie, and is an equity holder and scientific advisory board (SAB) member for Neomorph Inc., TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. E.S.F. is a founder, SAB member, and equity holder of Civetta Therapeutics, Proximity Therapeutics, and Neomorph, Inc. (also board of directors). E.S.F. is an equity holder and SAB member for Avilar Therapeutics and Photys Therapeutics, an equity holder in Lighthorse Therapeutics, and a consultant to Odyssey, Novartis, Sanofi, EcoR1 Capital, Ajax Therapeutics, and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, and Astellas. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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