Biology:DNA (cytosine-5)-methyltransferase 3A

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

DNA (cytosine-5)-methyltransferase 3A is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene.[1][2]

This enzyme is responsible for de novo DNA methylation. Such function is to be distinguished from maintenance DNA methylation which ensures the fidelity of replication of inherited epigenetic patterns. DNMT3A forms part of the family of DNA methyltransferase enzymes, which consists of the protagonists DNMT1, DNMT3A and DNMT3B.[1][2]

While de novo DNA methylation modifies the information passed on by the parent to the progeny, it enables key epigenetic modifications essential for processes such as cellular differentiation and embryonic development, transcriptional regulation, heterochromatin formation, X-inactivation, imprinting and genome stability.[3]

DNMT3a is the gene most commonly found mutated in clonal hematopoiesis, a common aging-related phenomenon in which hematopoietic stem cells (HSCs) or other early blood cell progenitors contribute to the formation of a genetically distinct subpopulation of blood cells.[4][5][6]

Gene

DNMT3A is a 130 kDa protein encoded by 23 exons found on chromosome 2p23 in humans.[7] There exists a 98% homology between human and murine homologues.[2]

Due to splicing, there exist two main murine RNA isoforms, Dnmt3a1 and Dnmt3a2. These isoforms exist in different cell types.[8]

Protein structure

DNMT3A consists of three major protein domains: the Pro-Trp-Trp-Pro (PWWP) domain, the ATRX-DNMT3-DNMT3L (ADD) domain and the catalytic methyltransferase domain. The ADD domain serves as an inhibitor of the methyltransferase domain until DNMT3A binds to the unmodified lysine 4 of histone 3 (H3K4me0) for its de novo methylating activity.[8] This protein thus seems to have an inbuilt control mechanism targeting histones only for methylation. Finally, the methyltransferase domain is highly conserved, even among prokaryotes.[9]

Function

DNMT1 is responsible for maintenance DNA methylation while DNMT3A and DNMT3B carry out both maintenance – correcting the errors of DNMT1 – and de novo DNA methylation. After DNMT1 knockout in human cancer cells, these cells were found to retain their inherited methylation pattern,[10] which suggests maintenance activity by the expressed DNMT3s. DNMT3s show equal affinity for unmethylated and hemimethylated DNA substrates[10] while DNMT1 has a 10-40 fold preference for hemimethylated DNA.[11][12] The DNMT3s can bind to both forms and hence potentially do both maintenance and de novo modifications.

De novo methylation is the main recognized activity of DNMT3A, which is essential for processes such as those mentioned in the introductory paragraphs. Genetic imprinting prevents parthenogenesis in mammals,[13] and hence forces sexual reproduction and its multiple consequences on genetics and phylogenesis. DNMT3A is essential for genetic imprinting.[14]

Animal studies

In mice, this gene has shown reduced expression in ageing animals causes cognitive long-term memory decline.[15]

In Dnmt3a-/- mice, many genes associated with HSC self-renewal increase in expression and some fail to be appropriately repressed during differentiation.[16] This suggests abrogation of differentiation in hematopoietic stem cells (HSCs) and an increase in self-renewal cell-division instead. Indeed, it was found that differentiation was partially rescued if Dnmt3a-/- HSCs experienced an additional Ctnb1 knockdown – Ctnb1 codes for β-catenin, which participates in self-renewal cell division.[8]

Clinical relevance

This gene is frequently mutated in cancer, being one of 127 frequently mutated genes identified in the Cancer Genome Atlas project[17] DNMT3A mutations were most commonly seen in acute myeloid leukaemia (AML) where they occurred in just over 25% of cases sequenced. These mutations most often occur at position R882 in the protein and this mutation may cause loss of function.[18] DNMT3A mutations are associated with poor overall survival, suggesting that they have an important common effect on the potential of AML cells to cause lethal disease.[19] It has also been found that DNMT3A-mutated cell lines exhibit transcriptome instability, in that they have much more erroneous RNA splicing as compared to their isogenic wildtype counterparts.[20] Mutations in this gene are also associated with Tatton-Brown-Rahman syndrome, an over growth disorder.

Interactions

DNMT3A has been shown to interact with:


Model organisms

Model organisms have been used in the study of DNMT3A function. A conditional knockout mouse line called Dnmt3atm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[27] Male and female animals underwent a standardized phenotypic screen[28] to determine the effects of deletion.[29][30][31][32] Additional screens performed: - In-depth immunological phenotyping[33]

References

  1. ↑ 1.0 1.1 "Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases". Nat. Genet. 19 (3): 219–20. 1998. doi:10.1038/890. PMID 9662389. 
  2. ↑ 2.0 2.1 2.2 "Cloning, expression and chromosome locations of the human DNMT3 gene family". Gene 236 (1): 87–95. 1999. doi:10.1016/S0378-1119(99)00252-8. PMID 10433969. 
  3. ↑ Jia, Yuanhui; Li, Pishun; Fang, Lan; Zhu, Haijun; Xu, Liangliang; Cheng, Hao; Zhang, Junying; Li, Fei et al. (2016-04-12). "Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer". Cell Discovery 2: 16007. doi:10.1038/celldisc.2016.7. PMID 27462454. 
  4. ↑ Jan, Max; Ebert, Benjamin L.; Jaiswal, Siddhartha (1 January 2017). "Clonal hematopoiesis". Seminars in Hematology 54 (1): 43–50. doi:10.1053/j.seminhematol.2016.10.002. ISSN 1532-8686. PMID 28088988. 
  5. ↑ Sperling, Adam S.; Gibson, Christopher J.; Ebert, Benjamin L. (2017). "The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia". Nature Reviews Cancer 17 (1): 5–19. doi:10.1038/nrc.2016.112. ISSN 1474-1768. PMID 27834397. 
  6. ↑ Steensma, David P.; Bejar, Rafael; Jaiswal, Siddhartha; Lindsley, R. Coleman; Sekeres, Mikkael A.; Hasserjian, Robert P.; Ebert, Benjamin L. (2 July 2015). "Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes". Blood 126 (1): 9–16. doi:10.1182/blood-2015-03-631747. ISSN 1528-0020. PMID 25931582. 
  7. ↑ "The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors". Nucleic Acids Research 27 (11): 2291–8. June 1999. doi:10.1093/nar/27.11.2291. PMID 10325416. 
  8. ↑ 8.0 8.1 8.2 "DNMT3A in haematological malignancies". Nature Reviews. Cancer 15 (3): 152–65. 2015. doi:10.1038/nrc3895. PMID 25693834. 
  9. ↑ "Molecular and enzymatic profiles of mammalian DNA methyltransferases: structures and targets for drugs". Current Medicinal Chemistry 17 (33): 4052–71. 2010-01-01. doi:10.2174/092986710793205372. PMID 20939822. 
  10. ↑ 10.0 10.1 "CpG methylation is maintained in human cancer cells lacking DNMT1". Nature 404 (6781): 1003–7. April 2000. doi:10.1038/35010000. PMID 10801130. Bibcode: 2000Natur.404.1003R. 
  11. ↑ "Recombinant human DNA (cytosine-5) methyltransferase. I. Expression, purification, and comparison of de novo and maintenance methylation" (in en). The Journal of Biological Chemistry 274 (46): 33002–10. November 1999. doi:10.1074/jbc.274.46.33002. PMID 10551868. 
  12. ↑ "Baculovirus-mediated expression and characterization of the full-length murine DNA methyltransferase". Nucleic Acids Research 25 (22): 4666–73. November 1997. doi:10.1093/nar/25.22.4666. PMID 9358180. 
  13. ↑ "Genomic imprinting: parental influence on the genome". Nature Reviews Genetics 2 (1): 21–32. January 2001. doi:10.1038/35047554. PMID 11253064. 
  14. ↑ "Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting". Nature 429 (6994): 900–3. June 2004. doi:10.1038/nature02633. PMID 15215868. Bibcode: 2004Natur.429..900K. 
  15. ↑ "Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities". Nature Neuroscience 15 (8): 1111–3. August 2012. doi:10.1038/nn.3151. PMID 22751036. 
  16. ↑ "Dnmt3a is essential for hematopoietic stem cell differentiation". Nature Genetics 44 (1): 23–31. January 2012. doi:10.1038/ng.1009. PMID 22138693. 
  17. ↑ "Mutational landscape and significance across 12 major cancer types". Nature 502 (7471): 333–9. October 2013. doi:10.1038/nature12634. PMID 24132290. Bibcode: 2013Natur.502..333K. 
  18. ↑ "The role of mutations in epigenetic regulators in myeloid malignancies" (in en). Nature Reviews. Cancer 12 (9): 599–612. September 2012. doi:10.1038/nrc3343. PMID 22898539. 
  19. ↑ "DNMT3A mutations in acute myeloid leukemia". The New England Journal of Medicine 363 (25): 2424–33. December 2010. doi:10.1056/NEJMoa1005143. PMID 21067377. 
  20. ↑ Banaszak, LG; Giudice, V; Zhao, X; Wu, Z; Gao, S; Hosokawa, K; Keyvanfar, K; Townsley, DM et al. (2018). "Abnormal RNA splicing and genomic instability after induction of DNMT3A mutations by CRISPR/Cas9 gene editing". Blood Cells, Molecules and Diseases 69: 10–22. doi:10.1016/j.bcmd.2017.12.002. PMID 29324392. 
  21. ↑ 21.0 21.1 "Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases". The EMBO Journal 21 (15): 4183–95. August 2002. doi:10.1093/emboj/cdf401. PMID 12145218. 
  22. ↑ 22.0 22.1 22.2 22.3 "Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription". Nucleic Acids Research 32 (2): 598–610. 2004. doi:10.1093/nar/gkh195. PMID 14752048. 
  23. ↑ "Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin". Current Biology 13 (14): 1192–200. July 2003. doi:10.1016/s0960-9822(03)00432-9. PMID 12867029. 
  24. ↑ 24.0 24.1 "Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription". The EMBO Journal 20 (10): 2536–44. May 2001. doi:10.1093/emboj/20.10.2536. PMID 11350943. 
  25. ↑ "Myc represses transcription through recruitment of DNA methyltransferase corepressor". The EMBO Journal 24 (2): 336–46. January 2005. doi:10.1038/sj.emboj.7600509. PMID 15616584. 
  26. ↑ "The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase". Nucleic Acids Research 31 (9): 2305–12. May 2003. doi:10.1093/nar/gkg332. PMID 12711675. 
  27. ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. 
  28. ↑ 28.0 28.1 "International Mouse Phenotyping Consortium". http://www.mousephenotype.org/data/search?q=Dnmt3a#fq=*:*&facet=gene. 
  29. ↑ "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. June 2011. doi:10.1038/nature10163. PMID 21677750. 
  30. ↑ "Mouse library set to be knockout". Nature 474 (7351): 262–3. June 2011. doi:10.1038/474262a. PMID 21677718. 
  31. ↑ "A mouse for all reasons". Cell 128 (1): 9–13. January 2007. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  32. ↑ "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. July 2013. doi:10.1016/j.cell.2013.06.022. PMID 23870131. 
  33. ↑ 33.0 33.1 "Infection and Immunity Immunophenotyping (3i) Consortium". http://www.immunophenotyping.org/data/search?keys=Dnmt3a&field_gene_construct_tid=All. 

Further reading




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