Cited by 23Genomics and Chromatin DynamicsChromatin Remodeling and CancerEpigenetics and DNA Methylation

Pharmacological Restriction of Genomic Binding Sites Redirects PU.1 Pioneer Transcription Factor Activity

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Taylor, Samuel J., Stauber, Jacob, Bohorquez, Oliver, Tatsumi, Goichi, Kumari, Rajni, Chakraborty, Joyeeta, Bartholdy, Boris A., Schwenger, Emily +10 more·2024·Nature Genetics

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.

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  • PU.1 binds specific DNA sequences known as ETS motifs, which are located predominantly in enhancers but also in promoters of target genes.

    “PU.1, as an ETS family transcription factor, binds specific DNA sequences known as ETS motifs, which are located predominantly in the enhancers but also in the promoters of target genes [30, 31].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [30]

    The Results section (‘Pharmacological binding site restriction repositions PU.1’; page unavailable) reports enrichment of ETS motifs at PU.1 binding sites and identifies some sites in promoter regions. It does not establish that PU.1 binding sites are predominantly in enhancers, so that part of the claim is unsupported by our copy. (LLM, conf=0.84)

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Authors
Taylor, S. J., Stauber, J., Bohorquez, O., Tatsumi, G., Kumari, R., Chakraborty, J., Bartholdy, B. A., Schwenger, E., Sundaravel, S., Farahat, A. A., Wheat, J. C., Goldfinger, M., Verma, A., Kumar, A., Boykin, D. W., Stengel, K. R., Poon, G. M. K., & Steidl, U.
Affiliations
  • Albert Einstein College of Medicine (US)
  • Mansoura University (EG)
  • Georgia State University (US)
Corresponding author
Steidl, Ulrich
Venue
Nature Genetics
Published
2024-09-18
Volume
56
Issue
10
Pages
2213-2227
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W4402634386
Cited by
22
References
80
Citations by year
2026: 10 · 2025: 9 · 2024: 3
FWCI
2.99
Type
journal article
Language
en
Open access
Locations
  • Nature Genetics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (R35CA253127)
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL155178)
  • National Science Foundation (MCB2028902)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM142213)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
PU.1, pioneer transcription factors, transcription factor-DNA binding, cistrome, leukemia cell differentiation, hematologic malignancies, transcription factor localization, cell fate
MeSH terms
Proto-Oncogene Protein Spi-1, Binding Sites, Cell Differentiation, Humans, Protein Binding, Proto-Oncogene Proteins, Transcription Factors, Trans-Activators, Gene Regulatory Networks

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