Search

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.)

Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription., Competing Interests: Declaration of interests B.L.E. has received research funding from Celgene, Deerfield, Novartis, and Calico and consulting fees from GRAIL. He is a member of the Scientific Advisory Board and shareholder for Neomorph Inc., TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. A.S.S. received consulting fees from Adaptive Technologies. N.H.T. receives funding from the Novartis Research Foundation and is a member of the Scientific Advisory Board of Monte Rosa Therapeutics. K.A.D. is a consultant to Kronos Bio and Neomorph Inc. E.S.F. is a founder, Scientific Advisory Board (SAB) member, and equity holder of Civetta Therapeutics, Lighthorse Therapeutics, Proximity Therapeutics, and Neomorph, Inc. (also board of directors). B.L.E. and M.S. have received research funding from Calico Life Sciences LLC. E.S.F. is an equity holder and SAB member for Avilar Therapeutics and Photys 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery. By limiting activity to targeted loci, Syn-TEFs convert constituent modules from broad-spectrum inhibitors of transcription into gene-specific stimulators. Here we present Syn-TEF1, a molecule that actively enables transcription across repressive GAA repeats that silence frataxin expression in Friedreich's ataxia, a terminal neurodegenerative disease with no effective therapy. The modular design of Syn-TEF1 defines a general framework for developing a class of molecules that license transcription elongation at targeted genomic loci., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)