Variants of Cause Transcript-specific DNA Methylation Patterns and Affect Hematopoiesis

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2018 Dec 25

PMID 30582132

Citations 13

Authors

Tanja Bozic

Joana Frobel

Annamarija Raic

Fabio Ticconi

Chao-Chung Kuo

Stefanie Heilmann-Heimbach

Tamme W Goecke

Martin Zenke

Edgar Jost

Ivan G Costa

Wolfgang Wagner

Affiliations

Soon will be listed here.

Abstract

De novo DNA methyltransferase 3A (DNMT3A) plays pivotal roles in hematopoietic differentiation. In this study, we followed the hypothesis that alternative splicing of has characteristic epigenetic and functional sequels. Specific transcripts were either down-regulated or overexpressed in human hematopoietic stem and progenitor cells, and this resulted in complementary and transcript-specific DNA methylation and gene expression changes. Functional analysis indicated that, particularly, transcript 2 (coding for DNMT3A2) activates proliferation and induces loss of a primitive immunophenotype, whereas transcript 4 interferes with colony formation of the erythroid lineage. Notably, in acute myeloid leukemia expression of transcript 2 correlates with its in vitro DNA methylation and gene expression signatures and is associated with overall survival, indicating that variants also affect malignancies. Our results demonstrate that specific variants have a distinct epigenetic and functional impact. Particularly, DNMT3A2 triggers hematopoietic differentiation and the corresponding signatures are reflected in acute myeloid leukemia.

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References

Okano M, BELL D, Haber D, Li E . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999; 99(3):247-57. DOI: 10.1016/s0092-8674(00)81656-6. View

Chen T, Ueda Y, Xie S, Li E . A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation. J Biol Chem. 2002; 277(41):38746-54. DOI: 10.1074/jbc.M205312200. View

Weisenberger D, Velicescu M, Gonzales F, Tsai Y, Liang G, Jones P . Identification and characterization of alternatively spliced variants of DNA methyltransferase 3a in mammalian cells. Gene. 2002; 298(1):91-9. DOI: 10.1016/s0378-1119(02)00976-9. View

Walenda T, Bork S, Horn P, Wein F, Saffrich R, Diehlmann A . Co-culture with mesenchymal stromal cells increases proliferation and maintenance of haematopoietic progenitor cells. J Cell Mol Med. 2009; 14(1-2):337-50. PMC: 3837622. DOI: 10.1111/j.1582-4934.2009.00776.x. View

Broske A, Vockentanz L, Kharazi S, Huska M, Mancini E, Scheller M . DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet. 2009; 41(11):1207-15. DOI: 10.1038/ng.463. View

Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi Y . Array-based genomic resequencing of human leukemia. Oncogene. 2010; 29(25):3723-31. DOI: 10.1038/onc.2010.117. View

Choi S, Heo K, Byun H, An W, Lu W, Yang A . Identification of preferential target sites for human DNA methyltransferases. Nucleic Acids Res. 2010; 39(1):104-18. PMC: 3017615. DOI: 10.1093/nar/gkq774. View

Ley T, Ding L, Walter M, McLellan M, Lamprecht T, Larson D . DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010; 363(25):2424-33. PMC: 3201818. DOI: 10.1056/NEJMoa1005143. View

Walenda T, Bokermann G, Ventura Ferreira M, Piroth D, Hieronymus T, Neuss S . Synergistic effects of growth factors and mesenchymal stromal cells for expansion of hematopoietic stem and progenitor cells. Exp Hematol. 2011; 39(6):617-28. DOI: 10.1016/j.exphem.2011.02.011. View

10.

Van Emburgh B, Robertson K . Modulation of Dnmt3b function in vitro by interactions with Dnmt3L, Dnmt3a and Dnmt3b splice variants. Nucleic Acids Res. 2011; 39(12):4984-5002. PMC: 3130282. DOI: 10.1093/nar/gkr116. View

11.

Suetake I, Mishima Y, Kimura H, Lee Y, Goto Y, Takeshima H . Characterization of DNA-binding activity in the N-terminal domain of the DNA methyltransferase Dnmt3a. Biochem J. 2011; 437(1):141-8. DOI: 10.1042/BJ20110241. View

12.

Bibikova M, Barnes B, Tsan C, Ho V, Klotzle B, Le J . High density DNA methylation array with single CpG site resolution. Genomics. 2011; 98(4):288-95. DOI: 10.1016/j.ygeno.2011.07.007. View

13.

Chang Y, Sun L, Kokura K, Horton J, Fukuda M, Espejo A . MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a. Nat Commun. 2011; 2:533. PMC: 3286832. DOI: 10.1038/ncomms1549. View

14.

Challen G, Sun D, Jeong M, Luo M, Jelinek J, Berg J . Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet. 2011; 44(1):23-31. PMC: 3637952. DOI: 10.1038/ng.1009. View

15.

Ribeiro A, Pratcorona M, Erpelinck-Verschueren C, Rockova V, Sanders M, Abbas S . Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood. 2012; 119(24):5824-31. DOI: 10.1182/blood-2011-07-367961. View

16.

Ley T, Miller C, Ding L, Raphael B, Mungall A, Robertson A . Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368(22):2059-74. PMC: 3767041. DOI: 10.1056/NEJMoa1301689. View

17.

Jost E, Lin Q, Weidner C, Wilop S, Hoffmann M, Walenda T . Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia. Leukemia. 2013; 28(6):1227-34. PMC: 4051212. DOI: 10.1038/leu.2013.362. View

18.

Weidner C, Walenda T, Lin Q, Wolfler M, Denecke B, Costa I . Hematopoietic stem and progenitor cells acquire distinct DNA-hypermethylation during in vitro culture. Sci Rep. 2013; 3:3372. PMC: 3842544. DOI: 10.1038/srep03372. View

19.

Russler-Germain D, Spencer D, Young M, Lamprecht T, Miller C, Fulton R . The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell. 2014; 25(4):442-54. PMC: 4018976. DOI: 10.1016/j.ccr.2014.02.010. View

20.

Challen G, Sun D, Mayle A, Jeong M, Luo M, Rodriguez B . Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell. 2014; 15(3):350-364. PMC: 4163922. DOI: 10.1016/j.stem.2014.06.018. View