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Cited by 196Genomics and Chromatin DynamicsMuscle Physiology and DisordersEpigenetics and DNA Methylation

DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes

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Choi, Si Ho, Gearhart, Micah D., Cui, Ziyou, Bosnakovski, Darko, Kim, Minjee, Schennum, Natalie, Kyba, Michael·2016·Nucleic Acids Research
DOI 10.1093/nar/gkw141PMC PMC4914088
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Abstract

Ectopic expression of the double homeodomain transcription factor DUX4 causes facioscapulohumeral muscular dystrophy (FSHD). Mechanisms of action of DUX4 are currently unknown. Using immortalized human myoblasts with a titratable DUX4 transgene, we identify by mass spectrometry an interaction between the DUX4 C-terminus and the histone acetyltransferases p300/CBP. Chromatin immunoprecipitation shows that DUX4 recruits p300 to its target gene, ZSCAN4, displaces histone H3 from the center of its binding site, and induces H3K27Ac in its vicinity, but C-terminal deleted DUX4 does not. We show that a DUX4 minigene, bearing only the homeodomains and C-terminus, is transcriptionally functional and cytotoxic, and that overexpression of a nuclear targeted C-terminus impairs the ability of WT DUX4 to interact with p300 and to regulate target genes. Genomic profiling of DUX4, histone H3, and H3 modifications reveals that DUX4 binds two classes of loci: DNase accessible H3K27Ac-rich chromatin and inaccessible H3K27Ac-depleted MaLR-enriched chromatin. At this latter class, it acts as a pioneer factor, recruiting H3K27 acetyltransferase activity and opening the locus for transcription. In concert with local increased H3K27Ac, the strong H3K27Ac peaks at distant sites are significantly depleted of H3K27Ac, thus DUX4 uses its C-terminus to induce a global reorganization of H3K27 acetylation.

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  • The establishment and maintenance of patterns of histone and DNA modifications in a tissue-specific manner may be controlled by TFs directly or indirectly interacting with epigenetic modifiers, such as the histone acetylase CBP/p300.

    “The establishment and maintenance of patterns of histone and DNA modifications in a tissue-specific manner may be controlled by TFs directly or indirectly interacting with epigenetic modifiers (21), such as the histone acetylase CBP/p300 (22).”

    From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [22]

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Authors
Choi, S. H., Gearhart, M. D., Cui, Z., Bosnakovski, D., Kim, M., Schennum, N., & Kyba, M.
Affiliations
  • University of Minnesota (US)
  • Dongnam Institute of Radiological & Medical Sciences (KR)
Corresponding author
Kyba, Michael
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2016-03-06
Volume
44
Issue
11
Pages
5161-5173
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkw141
PMC
PMC4914088
OpenAlex
W2294583975
Cited by
196
References
1
Citations by year
2026: 7 · 2025: 17 · 2024: 31 · 2023: 34 · 2022: 22 · 2021: 22 · 2020: 25 · 2019: 8 · 2018: 10 · 2017: 15 · 2016: 5
FWCI
6.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Goce Delchev University Repository (Goce Delčev University of Štip) (acceptedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Muscular Dystrophy Association (MDA 4361)
  • FSH Society
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS083549)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR055685, R01AR055685)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
DUX4, facioscapulohumeral muscular dystrophy, P300, CBP, histone acetyltransferase, H3K27 acetylation, pioneer factors, chromatin accessibility, Zscan4, homeodomain transcription factor, histone modifications, myoblasts
MeSH terms
Acetylation, Binding Sites, Cell Line, Histones, Humans, Promoter Regions, Genetic, Protein Binding, Transcription, Genetic, Gene Expression, Genes, Reporter, Homeodomain Proteins, Myoblasts, Epigenesis, Genetic, Chromatin Immunoprecipitation, p300-CBP Transcription Factors, Protein Interaction Domains and Motifs, Epigenomics, High-Throughput Nucleotide Sequencing

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