The H3K27me3 Demethylase DUTX is a Suppressor of Notch- and Rb-dependent Tumors in Drosophila

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2010 Mar 10

PMID 20212086

Citations 68

Authors

Hans-Martin Herz

Laurence D Madden

Zhihong Chen

Clare Bolduc

Eugene Buff

Ravi Gupta

Ramana Davuluri

Ali Shilatifard

Iswar K Hariharan

Andreas Bergmann

Affiliations

Soon will be listed here.

Abstract

Trimethylated lysine 27 of histone H3 (H3K27me3) is an epigenetic mark for gene silencing and can be demethylated by the JmjC domain of UTX. Excessive H3K27me3 levels can cause tumorigenesis, but little is known about the mechanisms leading to those cancers. Mutants of the Drosophila H3K27me3 demethylase dUTX display some characteristics of Trithorax group mutants and have increased H3K27me3 levels in vivo. Surprisingly, dUTX mutations also affect H3K4me1 levels in a JmjC-independent manner. We show that a disruption of the JmjC domain of dUTX results in a growth advantage for mutant cells over adjacent wild-type tissue due to increased proliferation. The growth advantage of dUTX mutant tissue is caused, at least in part, by increased Notch activity, demonstrating that dUTX is a Notch antagonist. Furthermore, the inactivation of Retinoblastoma (Rbf in Drosophila) contributes to the growth advantage of dUTX mutant tissue. The excessive activation of Notch in dUTX mutant cells leads to tumor-like growth in an Rbf-dependent manner. In summary, these data suggest that dUTX is a suppressor of Notch- and Rbf-dependent tumors in Drosophila melanogaster and may provide a model for UTX-dependent tumorigenesis in humans.

Citing Articles

Double-strand breaks in facultative heterochromatin require specific movements and chromatin changes for efficient repair.

Wensveen M, Dixit A, van Schendel R, Kendek A, Lambooij J, Tijsterman M Nat Commun. 2024; 15(1):8984.

PMID: 39419979 PMC: 11487122. DOI: 10.1038/s41467-024-53313-2.

Loss of GATA6-mediated up-regulation of UTX promotes pancreatic tumorigenesis and progression.

Zhang H, Kong F, Kong X, Jiang T, Ma M, Zheng S Genes Dis. 2023; 11(2):921-934.

PMID: 37692474 PMC: 10491869. DOI: 10.1016/j.gendis.2023.01.019.

MLL3 regulates the tumor suppressor locus in liver cancer.

Zhu C, Soto-Feliciano Y, Morris J, Huang C, Koche R, Ho Y Elife. 2023; 12.

PMID: 37261974 PMC: 10279454. DOI: 10.7554/eLife.80854.

: a powerful model organism to explore histone modifications and their upstream regulations.

Yu Y, Wang S, Wang Z, Gao R, Lee J Epigenetics. 2023; 18(1):2211362.

PMID: 37196184 PMC: 10193919. DOI: 10.1080/15592294.2023.2211362.

Diverse and dynamic forms of gene regulation by the S. cerevisiae histone methyltransferase Set1.

Deshpande N, Bryk M Curr Genet. 2023; 69(2-3):91-114.

PMID: 37000206 DOI: 10.1007/s00294-023-01265-3.

References

Lee T, Jenner R, Boyer L, Guenther M, Levine S, Kumar R . Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006; 125(2):301-13. PMC: 3773330. DOI: 10.1016/j.cell.2006.02.043. View

Bracken A, Dietrich N, Pasini D, Hansen K, Helin K . Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006; 20(9):1123-36. PMC: 1472472. DOI: 10.1101/gad.381706. View

Boyer L, Plath K, Zeitlinger J, Brambrink T, Medeiros L, Lee T . Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006; 441(7091):349-53. DOI: 10.1038/nature04733. View

Tolhuis B, de Wit E, Muijrers I, Teunissen H, Talhout W, van Steensel B . Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nat Genet. 2006; 38(6):694-9. DOI: 10.1038/ng1792. View

Schwartz Y, Kahn T, Nix D, Li X, Bourgon R, Biggin M . Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nat Genet. 2006; 38(6):700-5. DOI: 10.1038/ng1817. View

Negre N, Hennetin J, Sun L, Lavrov S, Bellis M, White K . Chromosomal distribution of PcG proteins during Drosophila development. PLoS Biol. 2006; 4(6):e170. PMC: 1440717. DOI: 10.1371/journal.pbio.0040170. View

Squazzo S, OGeen H, Komashko V, Krig S, Jin V, Jang S . Suz12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res. 2006; 16(7):890-900. PMC: 1484456. DOI: 10.1101/gr.5306606. View

Bray S . Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006; 7(9):678-89. DOI: 10.1038/nrm2009. View

Klose R, Kallin E, Zhang Y . JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet. 2006; 7(9):715-27. DOI: 10.1038/nrg1945. View

10.

Sparmann A, van Lohuizen M . Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006; 6(11):846-56. DOI: 10.1038/nrc1991. View

11.

Schwartz Y, Pirrotta V . Polycomb silencing mechanisms and the management of genomic programmes. Nat Rev Genet. 2006; 8(1):9-22. DOI: 10.1038/nrg1981. View

12.

Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J . Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007; 39(2):232-6. DOI: 10.1038/ng1950. View

13.

Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce C, Nakamura T . Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol Cell Biol. 2006; 27(5):1889-903. PMC: 1820476. DOI: 10.1128/MCB.01506-06. View

14.

Pellock B, Buff E, White K, Hariharan I . The Drosophila tumor suppressors Expanded and Merlin differentially regulate cell cycle exit, apoptosis, and Wingless signaling. Dev Biol. 2007; 304(1):102-15. PMC: 1924969. DOI: 10.1016/j.ydbio.2006.12.021. View

15.

Moss T, Wallrath L . Connections between epigenetic gene silencing and human disease. Mutat Res. 2007; 618(1-2):163-74. PMC: 1892579. DOI: 10.1016/j.mrfmmm.2006.05.038. View

16.

Cho Y, Hong T, Hong S, Guo H, Yu H, Kim D . PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem. 2007; 282(28):20395-406. PMC: 2729684. DOI: 10.1074/jbc.M701574200. View

17.

Xu T, Rubin G . Analysis of genetic mosaics in developing and adult Drosophila tissues. Development. 1993; 117(4):1223-37. DOI: 10.1242/dev.117.4.1223. View

18.

Saucedo L, Edgar B . Filling out the Hippo pathway. Nat Rev Mol Cell Biol. 2007; 8(8):613-21. DOI: 10.1038/nrm2221. View

19.

Robertson G, Hirst M, Bainbridge M, Bilenky M, Zhao Y, Zeng T . Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods. 2007; 4(8):651-7. DOI: 10.1038/nmeth1068. View

20.

De Santa F, Totaro M, Prosperini E, Notarbartolo S, Testa G, Natoli G . The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. 2007; 130(6):1083-94. DOI: 10.1016/j.cell.2007.08.019. View