Targets and Genomic Constraints of Ectopic Dnmt3b Expression

Overview

Journal Elife

Specialty Biology

Date 2018 Nov 24

PMID 30468428

Citations 18

Authors

Yingying Zhang

Jocelyn Charlton

Rahul Karnik

Isabel Beerman

Zachary D Smith

Hongcang Gu

Patrick Boyle

Xiaoli Mi

Kendell Clement

Ramona Pop

Andreas Gnirke

Derrick J Rossi

Alexander Meissner

Affiliations

Soon will be listed here.

Abstract

DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation of the de novo DNA methyltransferase DNMT3B is frequently observed across cancer types, yet little is known about its ectopic genomic targets. Here, we used an inducible transgenic mouse model to delineate rules for abnormal DNMT3B targeting, as well as the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpG islands to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually non-overlapping at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation. Our genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a distributive activity of ectopically expressed Dnmt3b that leads to discordant CpG island hypermethylation and provides new insights for interpreting the cancer methylome.

Citing Articles

Genome-Wide Methylation Profiling of Peripheral T-Cell Lymphomas Identifies TRIP13 as a Critical Driver of Tumor Proliferation and Survival.

Nowialis P, Tobon J, Lopusna K, Opavska J, Badar A, Chen D Epigenomes. 2024; 8(3).

PMID: 39189258 PMC: 11348144. DOI: 10.3390/epigenomes8030032.

Connecting the dots: investigating the link between environmental, genetic, and epigenetic influences in metabolomic alterations in oral squamous cell carcinoma.

Gupta I, Badrzadeh F, Tsentalovich Y, Gaykalova D J Exp Clin Cancer Res. 2024; 43(1):239.

PMID: 39169426 PMC: 11337877. DOI: 10.1186/s13046-024-03141-5.

DNA methylation in mammalian development and disease.

Smith Z, Hetzel S, Meissner A Nat Rev Genet. 2024; 26(1):7-30.

PMID: 39134824 DOI: 10.1038/s41576-024-00760-8.

Genome-wide methylation profiling of Peripheral T-cell lymphomas identifies TRIP13 as a critical driver of tumor proliferation and survival.

Nowialis P, Tobon J, Lopusna K, Opavska J, Badar A, Chen D Res Sq. 2024; .

PMID: 38464090 PMC: 10925438. DOI: 10.21203/rs.3.rs-3971059/v1.

Dynamic antagonism between key repressive pathways maintains the placental epigenome.

Weigert R, Hetzel S, Bailly N, Haggerty C, Ilik I, Yung P Nat Cell Biol. 2023; 25(4):579-591.

PMID: 37024684 PMC: 10104784. DOI: 10.1038/s41556-023-01114-y.

References

Amara K, Ziadi S, Hachana M, Soltani N, Korbi S, Trimeche M . DNA methyltransferase DNMT3b protein overexpression as a prognostic factor in patients with diffuse large B-cell lymphomas. Cancer Sci. 2010; 101(7):1722-30. PMC: 11159814. DOI: 10.1111/j.1349-7006.2010.01569.x. View

Athanasiadou R, De Sousa D, Myant K, Merusi C, Stancheva I, Bird A . Targeting of de novo DNA methylation throughout the Oct-4 gene regulatory region in differentiating embryonic stem cells. PLoS One. 2010; 5(4):e9937. PMC: 2848578. DOI: 10.1371/journal.pone.0009937. View

Landau D, Clement K, Ziller M, Boyle P, Fan J, Gu H . Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia. Cancer Cell. 2014; 26(6):813-825. PMC: 4302418. DOI: 10.1016/j.ccell.2014.10.012. View

Baylin S, Jones P . A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011; 11(10):726-34. PMC: 3307543. DOI: 10.1038/nrc3130. View

Klein C, Botuyan M, Wu Y, Ward C, Nicholson G, Hammans S . Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet. 2011; 43(6):595-600. PMC: 3102765. DOI: 10.1038/ng.830. View

Weisenberger D, Velicescu M, Cheng J, Gonzales F, Liang G, Jones P . Role of the DNA methyltransferase variant DNMT3b3 in DNA methylation. Mol Cancer Res. 2004; 2(1):62-72. View

Hoadley K, Yau C, Wolf D, Cherniack A, Tamborero D, Ng S . Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014; 158(4):929-944. PMC: 4152462. DOI: 10.1016/j.cell.2014.06.049. View

Robertson K . DNA methylation and human disease. Nat Rev Genet. 2005; 6(8):597-610. DOI: 10.1038/nrg1655. View

Ziller M, Gu H, Muller F, Donaghey J, Tsai L, Kohlbacher O . Charting a dynamic DNA methylation landscape of the human genome. Nature. 2013; 500(7463):477-81. PMC: 3821869. DOI: 10.1038/nature12433. View

10.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

11.

Shaham O, Menuchin Y, Farhy C, Ashery-Padan R . Pax6: a multi-level regulator of ocular development. Prog Retin Eye Res. 2012; 31(5):351-76. DOI: 10.1016/j.preteyeres.2012.04.002. View

12.

Linhart H, Lin H, Yamada Y, Moran E, Steine E, Gokhale S . Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev. 2007; 21(23):3110-22. PMC: 2081977. DOI: 10.1101/gad.1594007. View

13.

Gifford C, Ziller M, Gu H, Trapnell C, Donaghey J, Tsankov A . Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell. 2013; 153(5):1149-63. PMC: 3709577. DOI: 10.1016/j.cell.2013.04.037. View

14.

Otani J, Nankumo T, Arita K, Inamoto S, Ariyoshi M, Shirakawa M . Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep. 2009; 10(11):1235-41. PMC: 2775176. DOI: 10.1038/embor.2009.218. View

15.

Tanay A, ODonnell A, Damelin M, Bestor T . Hyperconserved CpG domains underlie Polycomb-binding sites. Proc Natl Acad Sci U S A. 2007; 104(13):5521-6. PMC: 1838490. DOI: 10.1073/pnas.0609746104. View

16.

Cunningham F, Amode M, Barrell D, Beal K, Billis K, Brent S . Ensembl 2015. Nucleic Acids Res. 2014; 43(Database issue):D662-9. PMC: 4383879. DOI: 10.1093/nar/gku1010. View

17.

Grant C, Bailey T, Noble W . FIMO: scanning for occurrences of a given motif. Bioinformatics. 2011; 27(7):1017-8. PMC: 3065696. DOI: 10.1093/bioinformatics/btr064. View

18.

Beard C, Hochedlinger K, Plath K, Wutz A, Jaenisch R . Efficient method to generate single-copy transgenic mice by site-specific integration in embryonic stem cells. Genesis. 2006; 44(1):23-8. DOI: 10.1002/gene.20180. View

19.

Liao J, Karnik R, Gu H, Ziller M, Clement K, Tsankov A . Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat Genet. 2015; 47(5):469-78. PMC: 4414868. DOI: 10.1038/ng.3258. View

20.

Li E, Bestor T, Jaenisch R . Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992; 69(6):915-26. DOI: 10.1016/0092-8674(92)90611-f. View