Cited by 36Genomics and Chromatin DynamicsChromatin Remodeling and CancerHematopoietic Stem Cell Transplantation

A c-Myb mutant causes deregulated differentiation due to impaired histone binding and abrogated pioneer factor function

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Fuglerud, Bettina M., Lemma, Roza B., Wanichawan, Pimthanya, Sundaram, Arvind Y. M., Eskeland, Ragnhild, Gabrielsen, Odd S.·2017·Nucleic Acids Research

Abstract

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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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
Published
2017-05-02
Volume
45
Issue
13
Pages
7681-7696
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
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
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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