Blockade of primary genomic binding sites with small molecules causes redistribution of the transcription factor PU.1 to alternative binding sites; its transcriptional activity at these sites activates secondary gene networks that drive myeloid cell differentiation.
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References
Scott, E. W. et al. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265, 1573–1577 (1994). A paper reporting the essential role of PU.1 in controlling hematopoietic lineage fate.
Will, B. et al. Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. Nat. Med. 21, 1172–1181 (2015). A paper describing the role of PU.1 in driving the development of myeloid leukemia.
Munde, M. et al. Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines. Nucleic Acids Res. 42, 1379 (2014). A paper describing how heterocyclic diamidines block PU.1–DNA interactions through minor groove interference.
Antony-Debré, I. et al. Pharmacological inhibition of the transcription factor PU.1 in leukemia. J. Clin. Invest. 127, 4297–4313 (2017). A paper describing the proof-of-concept use of heterocyclic diamidines to target PU.1 networks in AML.
Pham, T. H. et al. Mechanisms of in vivo binding site selection of the hematopoietic master transcription factor PU.1. Nucleic Acids Res. 41, 6391–6402 (2013). A paper highlighting the affinity of PU.1 for its genomic binding sites.
Minderjahn, J. et al. Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1. Nat. Commun. 11, 402 (2020). A paper highlighting the non-classical pioneer transcription factor ability of PU.1.
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This is a summary of: Taylor, S. J. et al. Pharmacological restriction of genomic binding sites redirects PU.1 pioneer transcription factor activity. Nat. Genet. https://doi.org/10.1038/s41588-024-01911-7 (2024).
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Chemical restriction of PU.1 genomic binding sites activates alternate gene networks. Nat Genet 56, 2012–2013 (2024). https://doi.org/10.1038/s41588-024-01912-6
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DOI: https://doi.org/10.1038/s41588-024-01912-6
