Pharmacological restriction of genomic binding sites redirects PU.1 pioneer transcription factor activity.

Autor: Taylor SJ; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Stauber J; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Bohorquez O; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Tatsumi G; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Kumari R; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Chakraborty J; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Bartholdy BA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Schwenger E; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Sundaravel S; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Farahat AA; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.; Master of Pharmaceutical Sciences Program, California Northstate University, Elk Grove, CA, USA., Wheat JC; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA., Goldfinger M; Department of Oncology, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.; Blood Cancer Institute, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA., Verma A; Department of Oncology, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.; Blood Cancer Institute, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.; Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.; Department of Medicine, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA., Kumar A; Department of Chemistry, Georgia State University, Atlanta, GA, USA., Boykin DW; Department of Chemistry, Georgia State University, Atlanta, GA, USA., Stengel KR; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.; Blood Cancer Institute, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.; Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA., Poon GMK; Department of Chemistry, Georgia State University, Atlanta, GA, USA.; Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA., Steidl U; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA. ulrich.steidl@einsteinmed.edu.; Department of Oncology, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA. ulrich.steidl@einsteinmed.edu.; Blood Cancer Institute, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA. ulrich.steidl@einsteinmed.edu.; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA. ulrich.steidl@einsteinmed.edu.; Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. ulrich.steidl@einsteinmed.edu.; Department of Medicine, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA. ulrich.steidl@einsteinmed.edu.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2024 Oct; Vol. 56 (10), pp. 2213-2227. Date of Electronic Publication: 2024 Sep 18.
DOI: 10.1038/s41588-024-01911-7
Abstrakt: Transcription factor (TF) DNA-binding dynamics govern cell fate and identity. However, our ability to pharmacologically control TF localization is limited. Here we leverage chemically driven binding site restriction leading to robust and DNA-sequence-specific redistribution of PU.1, a pioneer TF pertinent to many hematopoietic malignancies. Through an innovative technique, 'CLICK-on-CUT&Tag', we characterize the hierarchy of de novo PU.1 motifs, predicting occupancy in the PU.1 cistrome under binding site restriction. Temporal and single-molecule studies of binding site restriction uncover the pioneering dynamics of native PU.1 and identify the paradoxical activation of an alternate target gene set driven by PU.1 localization to second-tier binding sites. These transcriptional changes were corroborated by genetic blockade and site-specific reporter assays. Binding site restriction and subsequent PU.1 network rewiring causes primary human leukemia cells to differentiate. In summary, pharmacologically induced TF redistribution can be harnessed to govern TF localization, actuate alternate gene networks and direct cell fate.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: