A c-Myb mutant causes deregulated differentiation due to impaired histone binding and abrogated pioneer factor function
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The transcription factor c-Myb is involved in early differentiation and proliferation of haematopoietic cells, where it operates as a regulator of self-renewal and multi-lineage differentiation. Deregulated c-Myb plays critical roles in leukaemias and other human cancers. Due to its role as a master regulator, we hypothesized it might function as a pioneer transcription factor. Our approach to test this was to analyse a mutant of c-Myb, D152V, previously reported to cause haematopoietic defects in mice by an unknown mechanism. Our transcriptome data from K562 cells indicates that this mutation specifically affects c-Myb's ability to regulate genes involved in differentiation, causing failure in c-Myb's ability to block differentiation. Furthermore, we see a major effect of this mutation in assays where chromatin opening is involved. We show that each repeat in the minimal DNA-binding domain of c-Myb binds to histones and that D152V disrupts histone binding of the third repeat. ATAC-seq data indicates this mutation impairs the ability of c-Myb to cause chromatin opening at specific sites. Taken together, our findings support that c-Myb acts as a pioneer factor and show that D152V impairs this function. The D152V mutant is the first mutant of a transcription factor specifically destroying pioneer factor function.
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SOX9 harbours the pioneer TF ability to engage target sites in closed chromatin.
“Our results suggests that SOX9 harbours this ability but, as observed with other pioneer TFs (47,69,70), not all SOX9 binding events result in opening of chromatin.”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [70]
The Introduction defines pioneer transcription factors as able to associate with closed chromatin, and the Discussion presents evidence of pioneer activity for c-Myb. Neither passage establishes that SOX9 has this ability; the citing sentence presents that as the citing authors’ own result, not a finding of this source. (LLM, conf=0.84)
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Boontanrart, M. Y., Schröder, M., Stehli, G., Banović, M., Wyman, S. K., Lew, R. J., Bordi, M., Gowen, B. G., DeWitt, M. A., & Corn, J. E. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107993 · Cited by 38 · see citing works
SOX9 reprograms endothelial cells by altering the chromatin landscape
Fuglerud, B. M., Drissler, S., Lotto, J., Stephan, T. L., Thakur, A., Cullum, R., & Hoodless, P. A. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac652 · Cited by 35 · see citing works
“Our results suggests that SOX9 harbours this ability but, as observed with other pioneer TFs (47,69,70), not all SOX9 binding events result in opening of chromatin.”
ResultSelf-citationFuglerud, B. M., Ledsaak, M., Rogne, M., Eskeland, R., & Gabrielsen, O. S. (2018) · Epigenetics & Chromatin · doi:10.1186/s13072-018-0208-y · Cited by 34 · see citing works
Self-citationBibliometric Analysis of ATAC-Seq and Its Use in Cancer Biology via Nucleic Acid Detection
Zhao, Y., Zhang, X., Song, Z., Wei, D., Wang, H., Chen, W., Sun, G., Ma, W., & Chen, K. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.584728 · Cited by 28 · see citing works
Regulation of MYB by distal enhancer elements in human myeloid leukemia
Li, M., Jiang, P., Cheng, K., Zhang, Z., Lan, S., Li, X., Zhao, L., Wang, Y., Wang, X., Chen, J., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03515-z · Cited by 25 · see citing works
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Rodríguez-Castañeda, F., Lemma, R. B., Cuervo, I., Bengtsen, M., Moen, L. M., Ledsaak, M., Eskeland, R., & Gabrielsen, O. S. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002844 · Cited by 20 · see citing works
Self-citationChromatin occupancy and target genes of the haematopoietic master transcription factor MYB
Lemma, R. B., Ledsaak, M., Fuglerud, B. M., Sandve, G. K., Eskeland, R., & Gabrielsen, O. S. (2021) · Scientific Reports · doi:10.1038/s41598-021-88516-w · Cited by 17 · see citing works
Self-citationClarke, M. L., Lemma, R. B., Walton, D. S., Volpe, G., Noyvert, B., Gabrielsen, O. S., & Frampton, J. (2023) · Blood · doi:10.1182/blood.2022019138 · Cited by 19 · see citing works
Self-citationHuang, J., Fehr, A., Jäwert, F., Nilsson, J. A., Morris, L. G. T., Stenman, G., & Andersson, M. K. (2024) · Oral Oncology · doi:10.1016/j.oraloncology.2024.106763 · Cited by 12 · see citing works
Increased MYB alternative promoter usage is associated with relapse in acute lymphoblastic leukemia
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Intramolecular interaction of B‐MYB is regulated through Ser‐577 phosphorylation
Werwein, E., Biyanee, A., & Klempnauer, K. (2020) · FEBS Letters · doi:10.1002/1873-3468.13940 · Cited by 9 · see citing works
Halblander, F. N., Meng, F. W., & Murphy, P. J. (2023) · Developmental Biology · doi:10.1016/j.ydbio.2023.12.010 · Cited by 8 · see citing works
c-Myb regulates tumorigenic potential of embryonal rhabdomyosarcoma cells
Kašpar, P., Procházka, J., Blažíková, M., Juhasz, A., Novosadová, V., & Sedláček, R. (2019) · Scientific Reports · doi:10.1038/s41598-019-42684-y · Cited by 8 · see citing works
c-Myb Dominates TBK1-Mediated Endotoxin Tolerance in Kupffer Cells by Negatively Regulating DTX4
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Costa, J. R., Li, Y., Anuar, N. Z., O’Connor, D., Rahman, S., Rapoz-D’Silva, T., Fung, K. T. M., Pocock, R., Li, Z., Henderson, S. R., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115705 · Cited by 5 · see citing works
MYB: A Key Transcription Factor in the Hematopoietic System Subject to Many Levels of Control
Lemma, R. B., Fuglerud, B. M., Frampton, J., & Gabrielsen, O. S. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-62731-6_1 · Cited by 5 · see citing works
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Self-citationApplication of fluorescent probe for labile heme quantification in physiological dynamics
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Transcriptional regulatory program controlled by MYB in T-cell acute lymphoblastic leukemia
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ATAC-seq signal processing and recurrent neural networks can identify RNA polymerase activityPreprint
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Mechanism of SUMO repression of the transcription factor c-Myb – the role of SUMO acetylation
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Flipping the Hemoglobin Switch and Discovering Regulators Involved in Fetal Hemoglobin Reactivation
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Self-citationPTPRJ Drives Clonal Selection in CEBPA-mutated AMLPreprint
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Proteome-wide Multi-omics Profiling of Osteosarcoma Transcription Factor Networks
Thang, N. X., Martinsen, E., Abdelhalim, M., Tran, T. T., Ledsaak, M., Rogne, M., Thiede, B., & Eskeland, R. (2026) · Journal of Molecular Biology · doi:10.1016/j.jmb.2026.169959
Self-citation
- Authors
- Fuglerud, B. M., Lemma, R. B., Wanichawan, P., Sundaram, A. Y. M., Eskeland, R., & Gabrielsen, O. S.
- Affiliations
- University of Oslo (NO)
- Oslo University Hospital (NO)
- Corresponding author
- Gabrielsen, Odd S.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-05-02
- Volume
- 45
- Issue
- 13
- Pages
- 7681-7696
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC5570105
- OpenAlex
- W2610584680
- Cited by
- 36
- References
- 85
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 5 · 2018: 3
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc)
- Funders
- Universitetet i Oslo
- 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
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- MYB, pioneer transcription factors, histone binding, chromatin opening, hematopoietic differentiation, K562 cells, ATAC-seq, chromatin accessibility, transcription factor mutants
- MeSH terms
- Protein Domains, Animals, Cell Differentiation, Chromatin, Erythropoiesis, Histones, Humans, Models, Molecular, Mutation, Protein Binding, Amino Acid Substitution, K562 Cells, Genes, myb, Proto-Oncogene Proteins c-myb, Mutant Proteins, Mice, Gene Knockdown Techniques
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