CoChat
Sign Up
Cited by 79Epigenetics and DNA MethylationCancer-related gene regulationGenomics and Chromatin Dynamics

Protein Complex Interactor Analysis and Differential Activity of KDM3 Subfamily Members Towards H3K9 Methylation

Open access
Brauchle, Michael, Yao, Zhiping, Arora, Rishi, Thigale, Sachin, Clay, Ieuan, Inverardi, Bruno, Fletcher, Joy, Taslimi, Paul +7 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0060549PMC PMC3623819
Open this paper in CoChat — free accountOpen PDF

Abstract

Histone modifications play an important role in chromatin organization and gene regulation, and their interpretation is referred to as epigenetic control. The methylation levels of several lysine residues in histone tails are tightly controlled, and JmjC domain-containing proteins are one class of broadly expressed enzymes catalyzing methyl group removal. However, several JmjC proteins remain uncharacterized, gaps persist in understanding substrate recognition, and the integration of JmjC proteins into signaling pathways is just emerging. The KDM3 subfamily is an evolutionarily conserved group of histone demethylase proteins, thought to share lysine substrate specificity. Here we use a systematic approach to compare KDM3 subfamily members. We show that full-length KDM3A and KDM3B are H3K9me1/2 histone demethylases whereas we fail to observe histone demethylase activity for JMJD1C using immunocytochemical and biochemical approaches. Structure-function analyses revealed the importance of a single amino acid in KDM3A implicated in the catalytic activity towards H3K9me1/2 that is not conserved in JMJD1C. Moreover, we use quantitative proteomic analyses to identify subsets of the interactomes of the 3 proteins. Specific interactor candidates were identified for each of the three KDM3 subfamily members. Importantly, we find that SCAI, a known transcriptional repressor, interacts specifically with KDM3B. Taken together, we identify substantial differences in the biology of KDM3 histone demethylases, namely enzymatic activity and protein-protein interactions. Such comparative approaches pave the way to a better understanding of histone demethylase specificity and protein function at a systems level and are instrumental in identifying the more subtle differences between closely related proteins.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0060549

Cites

5 of 5 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • KDM3B is a JumonjiC domain-containing histone demethylase with specificity toward H3K9 and is involved in gene activation in leukemia cells.

    “KDM3B was recently characterized as a member of the JumonjiC domain-containing histone demethylases that shows specificity toward H3K9 and is involved gene activation in leukemia cells [25, 26]”

    From Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling (2014) · cites this paper as [25]

    The Results (page unavailable) identify KDM3B as a JmjC-domain-containing demethylase and show that full-length KDM3B demethylates H3K9me1/2. Our copy does not report gene activation in leukemia cells; it mentions leukemia in the title of a cited study in the References, but does not establish that part of the claim itself. (LLM, conf=0.90)

    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

Flagged first, then by citations

Research works printed but not linked: 46

  1. [2]Kouzarides T (2007) Chromatin modifications and their function. Cell 128: 693– 705. 17320507
  2. [3]Jenuwein T, Allis CD (2001) Translating the histone code. Science 293: 1074– 1080. 11498575
  3. [4]Moazed D (2011) Mechanisms for the inheritance of chromatin states. Cell 146: 510– 518. 21854979 PMC3244757
  4. [6]Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447: 407– 412. 17522673
  5. [7]Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6: 838– 849. 16261189
  6. [8]Mosammaparast N, Shi Y (2010) Reversal of Histone Methylation: Biochemical and Molecular Mechanisms of Histone Demethylases. Annu Rev Biochem 79: 155– 179. 20373914
  7. [9]Kooistra SM, Helin K (2012) Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol 13: 297– 311. 22473470
  8. [10]Lu F, Li G, Cui X, Liu C, Wang XJ, et al (2008) Comparative analysis of JmjC domain-containing proteins reveals the potential histone demethylases in Arabidopsis and rice. J Integrative Plant Biol 50: 886– 896. 18713399
  9. [11]Saze H, Shiraishi A, Miura A, Kakutani T (2008) Control of genic DNA methylation by a jmjC domain-containing protein in Arabidopsis thaliana. Science 319: 462– 465. 18218897
  10. [12]Inagaki S, Miura-Kamio A, Nakamura Y, Lu F, Cui X, et al (2010) Autocatalytic differentiation of epigenetic modifications within the Arabidopsis genome. EMBO J 29: 3496– 3506. 20834229 PMC2964174
  11. [13]Curtis BJ, Zraly CB, Marenda DR, Dingwall AK (2011) Histone lysine demethylases function as co-repressors of SWI/SNF remodeling activities during Drosophila wing development. Dev Biol 350: 534– 547. 21146519
  12. [14]Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, et al (2006) JHDM2A, a JmjC-containing H3K9 dernethylase, facilitates transcription activation by androgen receptor. Cell 125: 483– 495. 16603237
  13. [15]Tateishi K, Okada Y, Kallin EM, Zhang Y (2009) Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458: 757– 761. 19194461 PMC4085783
  14. [16]Okada Y, Scott G, Ray MK, Mishina Y, Zhang Y (2007) Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature 450: 119– 123. 17943087
  15. [17]Hu ZB, Gomes I, Horrigan SK, Kravarusic J, Mar B, et al (2001) A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31. Oncogene 20: 6946– 6954. 11687974
  16. [18]Wolf SS, Patchev VK, Obendorf M (2007) A novel variant of the putative demethylase gene, s-JMJD1C, is a coactivator of the AR. Arch Biochem Biophys 460: 56– 66. 17353003
  17. [19]Kim SM, Kim JY, Choe NW, Cho IH, Kim JR, et al (2010) Regulation of mouse steroidogenesis by WHISTLE and JMJD1C through histone methylation balance. Nucleic Acids Res 38: 6389– 6403. 20530532 PMC2965226
  18. [20]Klose RJ, Zhang Y (2007) Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8: 307– 318. 17342184
  19. [21]Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, et al (2011) Integrative genomics viewer. Nat Biotechnol 29: 24– 26. 21221095 PMC3346182
  20. [23]Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, et al (2006) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439: 811– 816. 16362057
  21. [24]Baba A, Ohtake F, Okuno Y, Yokota K, Okada M, et al (2011) PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B. Nat Cell Biol 13: 668– 675. 21532585
  22. [25]Hornbeck PV, Chabra I, Kornhauser JM, Skrzypek E, Zhang B (2004) PhosphoSite: A bioinformatics resource dedicated to physiological protein phosphorylation. Proteomics 4: 1551– 1561. 15174125
  23. [26]Hillringhaus L, Yue WW, Rose NR, Ng SS, Gileadi C, et al (2011) Structural and evolutionary basis for the dual substrate selectivity of human KDM4 histone demethylase family. J Biol Chem 286: 41616– 41625. 21914792 PMC3308871
  24. [27]Hou H, Yu H (2010) Structural insights into histone lysine demethylation. Curr Opin Struct Biol 20: 739– 748. 20970991 PMC3010374
  25. [28]Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, et al (2007) The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128: 889– 900. 17320163
  26. [29]Ross PL, Huang YLN, Marchese JN, Williamson B, Parker K, et al (2004) Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics 3: 1154– 1169. 15385600
  27. [30]Chook YM, Blobel G (2001) Karyopherins and nuclear import. Curr Opin Struct Biol 11: 703– 715. 11751052
  28. [31]Brandt DT, Baarlink C, Kitzing TM, Kremmer E, Ivaska J, et al (2009) SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of beta1-integrin Nat Cell Biol. 11: 557– 568. 19350017
  29. [32]Lu T, Jackson MW, Wang BL, Yang MJ, Chance MR, et al (2010) Regulation of NF-kappa B by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A 107: 46– 51. 20080798 PMC2806709
  30. [33]Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, et al (2009) Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science 325: 90– 93. 19574390
  31. [34]Chang B, Chen Y, Zhao Y, Bruick RK (2007) JMJD6 is a histone arginine demethylase. Science 318: 444– 447. 17947579
  32. [35]Hahn P, Wegener I, Burrells A, Bose J, Wolf A, et al (2010) Analysis of Jmjd6 cellular localization and testing for its involvement in histone demethylation. PLoS ONE 5: e13769. 21060799 PMC2966431
  33. [36]Pasini D, Cloos PAC, Walfridsson J, Olsson L, Bukowski JP, et al (2010) JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464: 306– 310. 20075857
  34. [38]Miller SA, Mohn SE, Weinmann AS (2010) Jmjd3 and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Mol Cell 40: 594– 605. 21095589 PMC3032266
  35. [39]Clements EG, Mohammad HP, Leadem BR, Easwaran H, Cai Y, et al (2012) DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes. Nucleic Acids Res 40: 4334– 4346. 22278882 PMC3378872
  36. [40]Hata K, Okano M, Lei H, Li E (2002) Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129: 1983– 1993. 11934864
  37. [42]Ng SS, Kavanagh KL, McDonough MA, Butler D, Pilka ES, et al (2007) Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. Nature 448: 87– 91. 17589501
  38. [43]Hsia DA, Tepper CG, Pochampalli MR, Hsia EY, Izumiya C, et al (2010) KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proc Natl Acad Sci U S A 107: 9671– 9676. 20457893 PMC2906833
  39. [44]Lee JW, Choi HS, Gyuris J, Brent R, Moore DD (1995) 2 Classes of Proteins Dependent on Either the Presence Or Absence of Thyroid-Hormone for Interaction with the Thyroid-Hormone Receptor. Mol Endocrinol 9: 243– 254. 7776974
  40. [45]Pasini D, Hansen KH, Christensen J, Agger K, Cloos PAC, et al (2008) Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2. Genes Dev 22: 1345– 1355. 18483221 PMC2377189
  41. [46]Li Q, Shi L, Gui B, Yu W, Wang J, et al (2011) Binding of the JmjC Demethylase JARID1B to LSD1/NuRD Suppresses Angiogenesis and Metastasis in Breast Cancer Cells by Repressing Chemokine CCL14. Cancer Res 71: 6899– 6908. 21937684
  42. [47]Tahiliani M, Mei PC, Fang R, Leonor T, Rutenberg M, et al (2007) The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature 447: 601– 605. 17468742
  43. [48]Lee MG, Norman J, Shilatifard A, Shiekhattar R (2007) Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein. Cell 128: 877– 887. 17320162
  44. [49]Wilsker D, Patsialou A, Dallas PB, Moran E (2002) ARID proteins: a diverse family of DNA binding proteins implicated in the control of cell growth, differentiation, and development. Cell Growth Differ 13: 95– 106. 11959810
  45. [50]Wigler M, Pellicer A, Silverstein S, Axel R, Urlaub G, et al (1979) DNA-mediated transfer of the adenine phosphoribosyltransferase locus into mammalian cells. Proc Natl Acad Sci U S A 76: 1373– 1376. 286319 PMC383253
  46. [51]Perkins DN, Pappin DJ, Creasy DM, Cottrell JS (1999) Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis 20: 3551– 3567. 10612281

Cited by

Sorted by citations

Authors
Brauchle, M., Yao, Z., Arora, R., Thigale, S., Clay, I., Inverardi, B., Fletcher, J., Taslimi, P., Acker, M. G., Gerrits, B., Voshol, J., Bauer, A., Schübeler, D., Bouwmeester, T., & Ruffner, H.
Affiliations
  • Novartis (Switzerland) (CH)
  • Novartis Institutes for BioMedical Research (CH)
  • Friedrich Miescher Institute (CH)
Corresponding author
  • Brauchle, Michael
  • Ruffner, Heinz
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-04-11
Volume
8
Issue
4
Pages
e60549
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0060549
PMC
PMC3623819
OpenAlex
W1980435226
Cited by
79
References
5
Citations by year
2026: 5 · 2025: 6 · 2024: 8 · 2023: 3 · 2022: 6 · 2021: 2 · 2020: 6 · 2019: 8 · 2018: 4 · 2017: 8 · 2016: 2 · 2015: 9 · 2014: 9 · 2013: 2
FWCI
3.29
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
Novartis
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
histone demethylase, H3K9 methylation, JmjC domain proteins, KDM3A, KDM3B, JMJD1C, protein-protein interaction, protein-protein interaction network, SCAI, catalytic activity, histone modifications, epigenetic regulation
MeSH terms
Histones, Humans, Methylation, Microscopy, Fluorescence, Oxidoreductases, N-Demethylating, Mass Spectrometry, Transcription Factors, Blotting, Western, DNA Primers, Epigenesis, Genetic, Immunoprecipitation, Jumonji Domain-Containing Histone Demethylases, HEK293 Cells

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