Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms.

Autor: Lambourne L; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Mattioli K; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Santoso C; Department of Biology, Boston University, Boston, MA, USA.; Bioinformatics Program, Boston University, Boston, MA, USA., Sheynkman G; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Inukai S; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Kaundal B; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Berenson A; Molecular Biology, Cell Biology & Biochemistry Program, Boston University, Boston, MA, USA., Spirohn-Fitzgerald K; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Bhattacharjee A; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Rothman E; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Shrestha S; Department of Biology, Boston University, Boston, MA, USA., Laval F; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; TERRA Teaching and Research Centre, University of Liège, Gembloux, Belgium.; Laboratory of Viral Interactomes, GIGA Institute, University of Liège, Liège, Belgium., Yang Z; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Bisht D; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Sewell JA; Department of Biology, Boston University, Boston, MA, USA., Li G; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Prasad A; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Harvard College, Cambridge MA, USA., Phanor S; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Lane R; Department of Biology, Boston University, Boston, MA, USA., Campbell DM; Bioinformatics Program, Boston University, Boston, MA, USA., Hunt T; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Balcha D; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Gebbia M; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.; Lunenfeld-Tanenbaum Research Institute (LTRI), Sinai Health System, Toronto, Ontario, Canada., Twizere JC; TERRA Teaching and Research Centre, University of Liège, Gembloux, Belgium.; Laboratory of Viral Interactomes, GIGA Institute, University of Liège, Liège, Belgium., Hao T; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Frankish A; Laboratory of Viral Interactomes, GIGA Institute, University of Liège, Liège, Belgium., Riback JA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Salomonis N; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Calderwood MA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Hill DE; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Sahni N; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Vidal M; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Bulyk ML; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Fuxman Bass JI; Department of Biology, Boston University, Boston, MA, USA.; Bioinformatics Program, Boston University, Boston, MA, USA.; Molecular Biology, Cell Biology & Biochemistry Program, Boston University, Boston, MA, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Apr 10. Date of Electronic Publication: 2024 Apr 10.
DOI: 10.1101/2024.03.12.584681
Abstrakt: Most human Transcription factors (TFs) genes encode multiple protein isoforms differing in DNA binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: "rewirers" and "negative regulators", both of which were associated with differentiation and cancer. Our results support a model wherein the relative expression levels of, and interactions involving, TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.
Databáze: MEDLINE