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

Samuel J. Taylor, Jacob Stauber, Oliver Bohorquez, Goichi Tatsumi, Rajni Kumari, Joyeeta Chakraborty, Boris A. Bartholdy, Emily Schwenger, Sriram Sundaravel, Abdelbasset A. Farahat, Justin C. Wheat, Mendel Goldfinger, Amit Verma, Arvind Kumar, David W. Boykin, Kristy R. Stengel, Gregory M.K. Poon, Ulrich Steidl

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2213-2227
Number of pages15
JournalNature Genetics
Volume56
Issue number10
DOIs
StatePublished - Oct 2024

ASJC Scopus subject areas

  • Genetics

Fingerprint

Dive into the research topics of 'Pharmacological restriction of genomic binding sites redirects PU.1 pioneer transcription factor activity'. Together they form a unique fingerprint.

Cite this