Active Genes Are Tri-Methylated at K4 of Histone H3
Abstract
Lysine methylation of histones in vivo occurs in three states: mono-, di- and tri-methyl. Histone H3 has been found to be di-methylated at lysine 4 (K4) in active euchromatic regions but not in silent heterochromatic sites. Here we show that the Saccharomyces cerevisiae Set1 protein can catalyse di- and tri-methylation of K4 and stimulate the activity of many genes. Using antibodies that discriminate between the di- and tri-methylated state of K4 we show that di-methylation occurs at both inactive and active euchromatic genes, whereas tri-methylation is present exclusively at active genes. It is therefore the presence of a tri-methylated K4 that defines an active state of gene expression. These findings establish the concept of methyl status as a determinant for gene activity and thus extend considerably the complexity of histone modifications.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Deposition of H3K4me3 at the 5' regions of actively transcribed genes is facilitated by trithorax group (trxG) protein complexes in coordination with the initiating form of RNA polymerase.
“The deposition of H3K4me3 at the 5 ′ regions of actively transcribed genes is facilitated by trithorax group (trxG) protein complexes in coordination with the initiating form of RNA polymerase [56,57].”
From Somaclonal Variation and Clonal Fidelity in Commercial Micropropagation: Challenges and Perspectives (2025) · cites this paper as [57]
Cites
Regulation of chromatin structure by site-specific histone H3 methyltransferases
Rea, S., Eisenhaber, F., O'Carroll, D., Strahl, B. D., Sun, Z.-W., Schmid, M., Opravil, S., Mechtler, K., Ponting, C. P., Allis, C. D., et al. (2000) · Nature · doi:10.1038/35020506 · Cited by 2,845 · see citing works
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
Flagged first, then by citations
Cited by
Sorted by citations
Histone demethylation mediated by the nuclear amine oxidase homolog LSD1
Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J. R., Cole, P. A., Casero, R. A., & Shi, Y. (2004) · Cell · doi:10.1016/j.cell.2004.12.012 · Cited by 4,051 · see citing works
Histone methylation: a dynamic mark in health, disease and inheritance
Greer, E. L., & Shi, Y. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3173 · Cited by 2,241 · see citing works
Pioneer transcription factors: establishing competence for gene expression
Zaret, K. S., & Carroll, J. S. (2011) · Genes & Development · doi:10.1101/gad.176826.111 · Cited by 1,589 · see citing works
Writing, erasing and reading histone lysine methylations
Hyun, K., Jeon, J., Park, K., & Kim, J. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.11 · Cited by 1,250 · see citing works
Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark
Ruthenburg, A. J., Allis, C. D., & Wysocka, J. (2007) · Molecular Cell · doi:10.1016/j.molcel.2006.12.014 · Cited by 1,147 · see citing works
Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin.
Vaquero, A., Scher, M., Lee, D., Erdjument-Bromage, H., Tempst, P., & Reinberg, D. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.08.031 · Cited by 916 · see citing works
De Bosscher, K., Vanden Berghe, W., & Haegeman, G. (2003) · Endocrine Reviews · doi:10.1210/er.2002-0006 · Cited by 898 · see citing works
Histones: annotating chromatin
Campos, E. I., & Reinberg, D. (2009) · Annual Review of Genetics · doi:10.1146/annurev.genet.032608.103928 · Cited by 852 · see citing works
Henry, K. W., Wyce, A., Lo, W.-S., Duggan, L. J., Emre, N. C. T., Kao, C.-F., Pillus, L., Shilatifard, A., Osley, M. A., & Berger, S. L. (2003) · Genes & Development · doi:10.1101/gad.1144003 · Cited by 714 · see citing works
Self-citationHistone acetylation and deacetylation in yeast
Kurdistani, S. K., & Grunstein, M. (2003) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1075 · Cited by 677 · see citing works
H3K4me3 breadth is linked to cell identity and transcriptional consistency
Benayoun, B. A., Pollina, E. A., Ucar, D., Mahmoudi, S., Karra, K., Wong, E. D., Devarajan, K., Daugherty, A. C., Kundaje, A. B., Mancini, E., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.027 · Cited by 536 · see citing works
A histone H3 methyltransferase controls epigenetic events required for meiotic prophase
Hayashi, K., Yoshida, K., & Matsui, Y. (2005) · Nature · doi:10.1038/nature04112 · Cited by 472 · see citing works
Ganal, S. C., Sanos, S. L., Kallfass, C., Oberle, K., Johner, C., Kirschning, C., Lienenklaus, S., Weiss, S., Staeheli, P., Aichele, P., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.05.020 · Cited by 484 · see citing works
Lund, A. H., & van Lohuizen, M. (2004) · Genes & Development · doi:10.1101/gad.1232504 · Cited by 489 · see citing works
NFATc1 Regulates PD-1 Expression upon T Cell Activation
Oestreich, K. J., Yoon, H., Ahmed, R., & Boss, J. M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.7.4832 · Cited by 416 · see citing works
Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex
McKinnell, I. W., Ishibashi, J., Le Grand, F., Punch, V. G. J., Addicks, G. C., Greenblatt, J. F., Dilworth, F. J., & Rudnicki, M. A. (2008) · Nature Cell Biology · doi:10.1038/ncb1671 · Cited by 380 · see citing works
Sun, J., Brand, M., Zenke, Y., Tashiro, S., Groudine, M., & Igarashi, K. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308083100 · Cited by 364 · see citing works
Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18
Kapoor, N., Liang, W., Marbán, E., & Cho, H. C. (2013) · Nature Biotechnology · doi:10.1038/nbt.2465 · Cited by 321 · see citing works
Chromatin and Transcription in Yeast
Rando, O. J., & Winston, F. (2012) · Genetics · doi:10.1534/genetics.111.132266 · Cited by 269 · see citing works
Maures, T. J., Greer, E. L., Hauswirth, A. G., & Brunet, A. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00738.x · Cited by 256 · see citing works
Histones: At the Crossroads of Peptide and Protein Chemistry
Müller, M. M., & Muir, T. W. (2015) · Chemical Reviews · doi:10.1021/cr5003529 · Cited by 247 · see citing works
Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health
Schagdarsurengin, U., & Steger, K. (2016) · Nature Reviews Urology · doi:10.1038/nrurol.2016.157 · Cited by 222 · see citing works
Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration
von Schimmelmann, M., Feinberg, P. A., Sullivan, J. M., Ku, S. M., Badimon, A., Duff, M. K., Wang, Z., Lachmann, A., Dewell, S., Ma'ayan, A., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4360 · Cited by 225 · see citing works
CHD8 Is an ATP-Dependent Chromatin Remodeling Factor That Regulates β-Catenin Target Genes
Thompson, B. A., Tremblay, V., Lin, G., & Bochar, D. A. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00322-08 · Cited by 208 · see citing works
Activation of DNA Damage Response Signaling by Condensed Chromatin
Burgess, R. C., Burman, B., Kruhlak, M. J., & Misteli, T. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.060 · Cited by 198 · see citing works
Histone methylation makes its mark on longevity
Han, S., & Brunet, A. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.11.001 · Cited by 204 · see citing works
Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs
Baker, E. K., Johnstone, R. W., Zalcberg, J. R., & El-Osta, A. (2005) · Oncogene · doi:10.1038/sj.onc.1208955 · Cited by 196 · see citing works
Zhao, C., Deng, Y., Liu, L., Yu, K., Zhang, L., Wang, H., He, X., Wang, J., Lu, C., Wu, L. N., et al. (2016) · Nature Communications · doi:10.1038/ncomms10883 · Cited by 154 · see citing works
Mehedint, M. G., Niculescu, M. D., Craciunescu, C. N., & Zeisel, S. H. (2010) · The FASEB Journal · doi:10.1096/fj.09-140145 · Cited by 167 · see citing works
Bihaqi, S. W., Huang, H., Wu, J., & Zawia, N. H. (2011) · Journal of Alzheimer’s Disease · doi:10.3233/jad-2011-111013 · Cited by 162 · see citing works
Zhao, C., Dong, C., Frah, M., Deng, Y., Marie, C., Zhang, F., Xu, L., Ma, Z., Dong, X., Lin, Y., et al. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.05.022 · Cited by 146 · see citing works
Peña, C. J., Neugut, Y. D., & Champagne, F. A. (2013) · Endocrinology · doi:10.1210/en.2013-1595 · Cited by 150 · see citing works
Epigenetic transcriptional memory
D’Urso, A., & Brickner, J. H. (2017) · Current Genetics · doi:10.1007/s00294-016-0661-8 · Cited by 130 · see citing works
Tosh, D. N., Fu, Q., Callaway, C. W., McKnight, R. A., McMillen, I. C., Ross, M. G., Lane, R. H., & Desai, M. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00052.2010 · Cited by 136 · see citing works
Attema, J. L., Papathanasiou, P., Forsberg, E. C., Xu, J., Smale, S. T., & Weissman, I. L. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704468104 · Cited by 134 · see citing works
RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes
Kiskinis, E., Hallberg, M., Christian, M., Olofsson, M., Dilworth, S. M., White, R., & Parker, M. G. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601908 · Cited by 111 · see citing works
Cao, Q., Wang, W., Williams, J. B., Yang, F., Wang, Z.-J., & Yan, Z. (2020) · Science Advances · doi:10.1126/sciadv.abc8096 · Cited by 108 · see citing works
Lamb, A. N., Rosenfeld, J. A., Neill, N. J., Talkowski, M. E., Blumenthal, I., Girirajan, S., Keelean-Fuller, D., Fan, Z., Pouncey, J., Stevens, C., et al. (2012) · Human Mutation · doi:10.1002/humu.22037 · Cited by 107 · see citing works
Gacek-Matthews, A., Berger, H., Sasaki, T., Wittstein, K., Gruber, C., Lewis, Z. A., & Strauss, J. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1006222 · Cited by 105 · see citing works
Xiong, H., Luo, Y., Wang, Q., Yu, X., & He, A. (2021) · Nature Methods · doi:10.1038/s41592-021-01129-z · Cited by 100 · see citing works
Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers
Makkonen, H., Kauhanen, M., Paakinaho, V., Jääskeläinen, T., & Palvimo, J. J. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp352 · Cited by 97 · see citing works
Nrf2 Transcription Factor Can Directly Regulate mTOR
Bendavit, G., Aboulkassim, T., Hilmi, K., Shah, S., & Batist, G. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.760249 · Cited by 95 · see citing works
Cruceanu, C., Alda, M., Nagy, C., Freemantle, E., Rouleau, G. A., & Turecki, G. (2013) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712000363 · Cited by 93 · see citing works
Santos, T., Ferreira, R., Maia, J., Agasse, F., Xapelli, S., Cortes, L., Bragança, J., Malva, J. O., Ferreira, L., & Bernardino, L. (2012) · ACS Nano · doi:10.1021/nn304541h · Cited by 92 · see citing works
Succinylation of H3K122 destabilizes nucleosomes and enhances transcription
Zorro Shahidian, L., Haas, M., Le Gras, S., Nitsch, S., Mourão, A., Geerlof, A., Margueron, R., Michaelis, J., Daujat, S., & Schneider, R. (2021) · The EMBO Reports · doi:10.15252/embr.202051009 · Cited by 92 · see citing works
Self-citationSerum response factor binding sites differ in three human cell types
Cooper, S. J., Trinklein, N. D., Nguyen, L., & Myers, R. M. (2007) · Genome Research · doi:10.1101/gr.5875007 · Cited by 76 · see citing works
Minireview: NAD+, a Circadian Metabolite with an Epigenetic Twist
Sassone-Corsi, P. (2012) · Endocrinology · doi:10.1210/en.2011-1535 · Cited by 71 · see citing works
Sun, J., Ishii, M., Ting, M.-C., & Maxson, R. (2013) · Development · doi:10.1242/dev.085225 · Cited by 57 · see citing works
MKL1 is an epigenetic modulator of TGF-β induced fibrogenesis
Fan, Z., Hao, C., Li, M., Dai, X., Qin, H., Li, J., Xu, H., Wu, X., Zhang, L., Fang, M., et al. (2015) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2015.07.013 · Cited by 47 · see citing works
Multi-omics integration strategies for animal epigenetic studies — A review
Kim, D.-Y., & Kim, J.-M. (2021) · Animal Bioscience · doi:10.5713/ab.21.0042 · Cited by 47 · see citing works
Somaclonal Variation and Clonal Fidelity in Commercial Micropropagation: Challenges and Perspectives
Majumder, S., Igamberdiev, A. U., & Debnath, S. C. (2025) · Agronomy · doi:10.3390/agronomy15061489 · Cited by 46 · see citing works
South, P. F., Harmeyer, K. M., Serratore, N. D., & Briggs, S. D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215768110 · Cited by 42 · see citing works
Chung, Y. S., Kim, H. J., Kim, T.-M., Hong, S.-H., Kwon, K.-R., An, S., Park, J.-H., Lee, S., & Oh, I.-H. (2009) · Blood · doi:10.1182/blood-2009-01-197780 · Cited by 43 · see citing works
Raman, S. B., Nguyen, M. H., Zhang, Z., Cheng, S., Jia, H. Y., Weisner, N., Iczkowski, K., & Clancy, C. J. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05121.x · Cited by 43 · see citing works
Gonadotropin gene transcription is activated by menin-mediated effects on the chromatin
Wijeweera, A., Haj, M., Feldman, A., Pnueli, L., Luo, Z., & Melamed, P. (2015) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2015.01.001 · Cited by 17 · see citing works
Kim, J., Park, S., Kwon, S., Lee, E.-J., & Lee, J.-S. (2021) · Virulence · doi:10.1080/21505594.2021.1980988 · Cited by 13 · see citing works
Law, M. J., & Finger, M. A. (2017) · G3 Genes|Genomes|Genetics · doi:10.1534/g3.117.039586 · Cited by 6 · see citing works
- Authors
- Santos-Rosa, H., Schneider, R., Bannister, A. J., Sherriff, J., Bernstein, B. E., Emre, N. C. T., Schreiber, S. L., Mellor, J., & Kouzarides, T.
- Affiliations
- Cancer Research UK (GB)
- University of Oxford (GB)
- Harvard University (US)
- The Wistar Institute (US)
- Corresponding author
- Kouzarides, Tony
- ORCID
- Venue
- Nature
- Published
- 2002-09
- Volume
- 419
- Issue
- 6905
- Pages
- 407-411
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2022936129
- Cited by
- 2,138
- References
- 2
- Citations by year
- 2026: 41 · 2025: 58 · 2024: 71 · 2023: 76 · 2022: 83 · 2021: 95 · 2020: 82 · 2019: 80 · 2018: 62 · 2017: 80 · 2016: 92 · 2015: 83 · 2014: 94 · 2013: 97 · 2012: 100
- FWCI
- 34.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- H3K4, trimethylation, histone methylation, euchromatin, heterochromatin, gene expression, Saccharomyces cerevisiae, histone modifications, chromatin
- MeSH terms
- Antibodies, DNA-Binding Proteins, Genes, Fungal, Histones, Inositol, Lysine, Methionine, Methylation, Histone-Lysine N-Methyltransferase, Saccharomyces cerevisiae, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Fungal, Gene Expression Profiling, Saccharomyces cerevisiae Proteins
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