IPMK regulates HDAC3 activity and histone H4 acetylation in human cells
Open accessAbstract
Histone deacetylases (HDACs) repress transcription by catalyzing the removal of acetyl groups from histones. Class 1 HDACs are activated by inositol phosphate signaling molecules in vitro , but it is unclear if this regulation occurs in human cells. Inositol Polyphosphate Multikinase (IPMK) is required for production of inositol hexakisphosphate (IP6), pentakisphosphate (IP5) and certain tetrakisphosphate (IP4) species, all known activators of Class 1 HDACs in vitro . Here, we generated IPMK knockout (IKO) human U251 glioblastoma cells, which decreased cellular inositol phosphate levels and increased histone H4-acetylation by mass spectrometry. ChIP-seq showed IKO increased H4-acetylation at IKO-upregulated genes, but H4-acetylation was unchanged at IKO-downregulated genes, suggesting gene-specific responses to IPMK knockout. HDAC deacetylase enzyme activity was decreased in HDAC3 immunoprecipitates from IKO vs . wild-type cells, while deacetylase activity of other Class 1 HDACs had no detectable changes in activity. Wild-type IPMK expression in IKO cells fully rescued HDAC3 deacetylase activity, while kinase-dead IPMK expression had no effect. Further, the deficiency in HDAC3 activity in immunoprecipitates from IKO cells could be fully rescued by addition of synthesized IP4 (Ins(1,4,5,6)P4) to the enzyme assay, while control inositol had no effect. These data suggest that cellular IPMK-dependent inositol phosphates are required for full HDAC3 enzyme activity and proper histone H4-acetylation. Implications for targeting IPMK in HDAC3-dependent diseases are discussed.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Depletion of IPMK in cells or mouse tissue significantly diminishes HDAC3 activation and results in increased histone acetylation.
“Recent research has shown that depletion of IPMK—responsible for synthesizing HOIPs—in cells or mouse tissue significantly diminishes HDAC3 activation and results in increased histone acetylation [78,79].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [79]
The Abstract and Figure 6 description report that IPMK deletion in human U251 cells decreased HDAC3 activity and increased histone H4 acetylation. The paper does not report those outcomes in mouse tissue; its Discussion mentions a mouse knockout only in connection with unchanged Class I HDAC protein levels. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Signaling to Chromatin through Histone Modifications
Cheung, P., Allis, C. D., & Sassone-Corsi, P. (2000) · Cell · doi:10.1016/s0092-8674(00)00118-5 · Cited by 989 · see citing works
Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate
Watson, P. J., Fairall, L., Santos, G. M., & Schwabe, J. W. R. (2012) · Nature · doi:10.1038/nature10728 · Cited by 505 · cited 2× · see citing works
“Class 1 HDACs were discovered by crystallography to interact with the inositol phosphate Ins(1,4,5,6)P4, which fortuitously co-purified with the protein in the crystal structure of HDAC3 11 .”
BackgroundA Role for Nuclear Inositol 1,4,5-Trisphosphate Kinase in Transcriptional Control
Odom, A. R., Stahlberg, A., Wente, S. R., & York, J. D. (2000) · Science · doi:10.1126/science.287.5460.2026 · Cited by 394 · see citing works
Modulation of ATP-Dependent Chromatin-Remodeling Complexes by Inositol Polyphosphates
Shen, X., Xiao, H., Ranallo, R., Wu, W.-H., & Wu, C. (2003) · Science · doi:10.1126/science.1078068 · Cited by 338 · see citing works
Sowd, G. A., Serrao, E., Wang, H., Wang, W., Fadel, H. J., Poeschla, E. M., & Engelman, A. N. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1524213113 · Cited by 249 · see citing works
Self-citationInsights into the activation mechanism of class I HDAC complexes by inositol phosphates
Watson, P. J., Millard, C. J., Riley, A. M., Robertson, N. S., Wright, L. C., Godage, H. Y., Cowley, S. M., Jamieson, A. G., Potter, B. V. L., & Schwabe, J. W. R. (2016) · Nature Communications · doi:10.1038/ncomms11262 · Cited by 244 · see citing works
El Alami, M., Messenguy, F., Scherens, B., & Dubois, E. (2003) · Molecular Microbiology · doi:10.1046/j.1365-2958.2003.03562.x · Cited by 83 · see citing works
Wahane, S., Zhou, X., Zhou, X., Guo, L., Friedl, M.-S., Kluge, M., Ramakrishnan, A., Shen, L., Friedel, C. C., Zhang, B., et al. (2021) · Science Advances · doi:10.1126/sciadv.abd8811 · Cited by 67 · see citing works
Flagged first, then by citations
Research works printed but not linked: 7
- Shears, S. B. et al. Defining Signal Transduction by Inositol Phosphates. in Sub-cellular biochemistry vol. 59 389-412 (2012).
- Shears, S. B. Molecular basis for the integration of inositol phosphate signaling pathways via human ITPK1. Adv Enzyme Regul 49, 87 (2009).
- Park, J. et al. Inositol polyphosphate multikinase mediates extinction of fear memory. Proceedings of the National Academy of Sciences 201812771 (2019) doi:10.1073/pnas.1812771116. · DOI
- Watson, P. J. et al. Insights into the activation mechanism of class I HDAC complexes by inositol phosphates. Nat Commun 7, 11262 (2016).
- Hale, A. T., Clarke, B. P. & York, J. D. Metabolic Labeling of Inositol Phosphates and Phosphatidylinositols in Yeast and Mammalian Cells. Methods Mol Biol 2091, 83 (2020).
- Anders, S., Pyl, P. T. & Huber, W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166 (2015).
- Wu, D. & Smyth, G. K. Camera: a competitive gene set test accounting for inter-gene correlation. Nucleic Acids Res 40, e133 (2012).
Cited by
Sorted by citations
From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease
Mishra, S. H., Chatterjee, S., Viera-Preval, L., & Guha, P. (2025) · Biomolecules · doi:10.3390/biom15091266 · Cited by 1 · see citing works
“Recent research has shown that depletion of IPMK—responsible for synthesizing HOIPs—in cells or mouse tissue significantly diminishes HDAC3 activation and results in increased histone acetylation [78,79].”
- Authors
- Sowd, G. A., Stivison, E. A., Chapagain, P., Hale, A. T., Poland, J. C., Rameh, L. E., & Blind, R. D.
- Affiliations
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- Corresponding author
- Blind, Raymond D.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2024-04-29
- PMC
- PMC11092501
- OpenAlex
- W4396498044
- Cited by
- 6
- References
- 8
- Citations by year
- 2026: 1 · 2025: 5
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM132592, R35GM156389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- inositol polyphosphate multikinase, HDAC3, histone H4 acetylation, inositol phosphates, inositol tetrakisphosphate, transcriptional repression
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
