Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells
Open accessAbstract
Epigenetic regulation of hematopoietic stem cells (HSCs) ensures lifelong production of blood and bone marrow. Recently, we reported that loss of de novo DNA methyltransferase Dnmt3a results in HSC expansion and impaired differentiation. Here, we report conditional inactivation of Dnmt3b in HSCs either alone or combined with Dnmt3a deletion. Combined loss of Dnmt3a and Dnmt3b was synergistic, resulting in enhanced HSC self-renewal and a more severe block in differentiation than in Dnmt3a-null cells, whereas loss of Dnmt3b resulted in a mild phenotype. Although the predominant Dnmt3b isoform in adult HSCs is catalytically inactive, its residual activity in Dnmt3a-null HSCs can drive some differentiation and generates paradoxical hypermethylation of CpG islands. Dnmt3a/Dnmt3b-null HSCs displayed activated β-catenin signaling, partly accounting for the differentiation block. These data demonstrate distinct roles for Dnmt3b in HSC differentiation and provide insights into complementary de novo methylation patterns governing regulation of HSC fate decisions.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
DNMT3A loss-of-function does not lead to global DNA methylation changes.
“This reinforces previous findings that DNMT3A loss-of-function does not lead to global DNA methylation changes (15,16,19)”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [16]
In Results, under “Ablation of Dnmt3a and Dnmt3b in HSCs drive localized DNA methylation loss,” the paper reports a global decrease in DNA methylation in Dnmt3a-knockout HSCs. It explains that an earlier analysis found no significant difference because that method was biased toward CpG-dense regions. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredMouse models show Dnmt3a loss-of-function skews hematopoietic stem cell fate decisions toward self-renewal, facilitating clonal expansion in the bone marrow.
“Mouse models show Dnmt3a loss-of-function skews HSC fate decisions toward self-renewal, facilitating clonal expansion in the bone marrow (BM; ref. 15,16).”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [16]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Targeted mutation of the DNA methyltransferase gene results in embryonic lethality
Li, E., Bestor, T. H., & Jaenisch, R. (1992) · Cell · doi:10.1016/0092-8674(92)90611-f · Cited by 3,984 · see citing works
Genome-scale DNA methylation maps of pluripotent and differentiated cells
Meissner, A., Mikkelsen, T. S., Gu, H., Wernig, M., Hanna, J., Sivachenko, A., Zhang, X., Bernstein, B. E., Nusbaum, C., Jaffe, D. B., et al. (2008) · Nature · doi:10.1038/nature07107 · Cited by 2,536 · see citing works
Flagged first, then by citations
Research works printed but not linked: 38
- Bamford S Dawson E Forbes S Clements J Pettett R Dogan A Flanagan A Teague J Futreal PA Stratton MR The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website British journal of cancer 2004 91 355 358 15188009 PMC2409828
- Beerman I Bock C Garrison BS Smith ZD Gu H Meissner A Rossi DJ Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging Cell Stem Cell 2013 12 413 425 23415915 PMC12163706
- Bestor TH Activation of mammalian DNA methyltransferase by cleavage of a Zn binding regulatory domain Embo J 1992 11 2611 2617 1628623 PMC556736
- Cancer Genome Atlas Research, N Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia N Engl J Med 2013 368 2059 2074 23634996 PMC3767041
- Challen GA Sun D Jeong M Luo M Jelinek J Berg JS Bock C Vasanthakumar A Gu H Xi Y Dnmt3a is essential for hematopoietic stem cell differentiation Nat Genet 2012 44 23 31 22138693 PMC3637952
- Chen T Ueda Y Dodge JE Wang Z Li E Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b Mol Cell Biol 2003 23 5594 5605 12897133 PMC166327
- Dodge JE Okano M Dick F Tsujimoto N Chen T Wang S Ueda Y Dyson N Li E Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization J Biol Chem 2005 280 17986 17991 15757890
- Figueroa ME Skrabanek L Li Y Jiemjit A Fandy TE Paietta E Fernandez H Tallman MS Greally JM Carraway H MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation Blood 2009 114 3448 3458 19652201 PMC2765680
- Gopalakrishnan S Van Emburgh BO Shan J Su Z Fields CR Vieweg J Hamazaki T Schwartz PH Terada N Robertson KD A novel DNMT3B splice variant expressed in tumor and pluripotent cells modulates genomic DNA methylation patterns and displays altered DNA binding Molecular cancer research: MCR 2009 7 1622 1634 19825994 PMC2783805
- Grossmann V Haferlach C Weissmann S Roller A Schindela S Poetzinger F Stadler K Bellos F Kern W Haferlach T The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL Genes Chromosomes Cancer 2013 52 410 422 23341344
- Gu C Bock C Mikkelsen TS Jager N Smith ZD Tomazou E Gnirke A Lander ES Meissner A Genome-scale DNA methylation mapping of clinical samples at single-nucleotide resolution Nat Methods 2010 7 133 136 20062050 PMC2860480
- Gu H Smith ZD Bock C Boyle P Gnirke A Meissner A Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling Nat Protoc 2011 6 468 481 21412275
- Hata K Okano M Lei H Li E Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice Development 2002 129 1983 1993 11934864
- Jaenisch R Jahner D Methylation, expression and chromosomal position of genes in mammals Biochim Biophys Acta 1984 782 1 9 6372865
- Jeong M Sun D Luo M Huang Y Challen GA Rodriguez B Zhang X Chavez L Wang H Hannah R Large conserved domains of low DNA methylation maintained by Dnmt3a Nat Genet 2013 PMC3920905 24270360
- Kirstetter P Anderson K Porse BT Jacobsen SE Nerlov C Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block Nat Immunol 2006 7 1048 1056 16951689
- Lei H Oh SP Okano M Juttermann R Goss KA Jaenisch R Li E De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells Development 1996 122 3195 3205 8898232
- Ley TJ Ding L Walter MJ McLellan MD Lamprecht T Larson DE Kandoth C Payton JE Baty J Welch J DNMT3A mutations in acute myeloid leukemia N Engl J Med 2010 363 2424 2433 21067377 PMC3201818
- Ng HH Bird A DNA methylation and chromatin modification Curr Opin Genet Dev 1999 9 158 163 10322130
- Okano M Bell DW Haber DA Li E DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development Cell 1999 99 247 257 10555141
- Okano M Xie S Li E Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases Nat Genet 1998 19 219 220 9662389
- Ostler KR Davis EM Payne SL Gosalia BB Exposito-Cespedes J Le Beau MM Godley LA Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins Oncogene 2007 26 5553 5563 17353906 PMC2435620
- Perry JM He XC Sugimura R Grindley JC Haug JS Ding S Li L Cooperation between both Wnt/{beta}-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion Genes Dev 2011 25 1928 1942 21890648 PMC3185965
- Peters SL Hlady RA Opavska J Klinkebiel D Pirruccello SJ Talmon GA Sharp JG Wu L Jaenisch R Simpson MA Tumor suppressor functions of Dnmt3a and Dnmt3b in the prevention of malignant mouse lymphopoiesis Leukemia 2014 28 1138 1142 24292811
- Reya T Duncan AW Ailles L Domen J Scherer DC Willert K Hintz L Nusse R Weissman IL A role for Wnt signalling in self-renewal of haematopoietic stem cells Nature 2003 423 409 414 12717450
- Scheller M Huelsken J Rosenbauer F Taketo MM Birchmeier W Tenen DG Leutz A Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation Nat Immunol 2006 7 1037 1047 16951686
- Shen L Kantarjian H Guo Y Lin E Shan J Huang X Berry D Ahmed S Zhu W Pierce S DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2010 28 605 613 20038729 PMC2815995
- Shen L Kondo Y Guo Y Zhang J Zhang L Ahmed S Shu J Chen X Waterland RA Issa JP Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters PLoS Genet 2007 3 2023 2036 17967063 PMC2041996
- Stein SJ Baldwin AS Deletion of the NF-kappaB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function Blood 2013 121 5015 5024 23670180 PMC3689248
- Surani MA Imprinting and the initiation of gene silencing in the germ line Cell 1998 93 309 312 9590162
- Tadokoro Y Ema H Okano M Li E Nakauchi H De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells J Exp Med 2007 204 715 722 17420264 PMC2118548
- Walter MJ Ding L Shen D Shao J Grillot M McLellan M Fulton R Schmidt H Kalicki-Veizer J O'Laughlin M Recurrent DNMT3A mutations in patients with myelodysplastic syndromes Leukemia 2011 25 1153 1158 21415852 PMC3202965
- Wilson NK Foster SD Wang X Knezevic K Schutte J Kaimakis P Chilarska PM Kinston S Ouwehand WH Dzierzak E Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators Cell Stem Cell 2010 7 532 544 20887958
- Wu H Coskun V Tao J Xie W Ge W Yoshikawa K Li E Zhang Y Sun YE Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes Science 2010 329 444 448 20651149 PMC3539760
- Xie S Wang Z Okano M Nogami M Li Y He WW Okumura K Li E Cloning, expression and chromosome locations of the human DNMT3 gene family Gene 1999 236 87 95 10433969
- Xie W Schultz MD Lister R Hou Z Rajagopal N Ray P Whitaker JW Tian S Hawkins RD Leung D Epigenomic analysis of multilineage differentiation of human embryonic stem cells Cell 2013 153 1134 1148 23664764 PMC3786220
- Yan XJ Xu J Gu ZH Pan CM Lu G Shen Y Shi JY Zhu YM Tang L Zhang XW Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia Nat Genet 2011 43 309 315 21399634
- Zhao C Xiu Y Ashton J Xing L Morita Y Jordan CT Boyce BF Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions Stem Cells 2012 30 709 718 22290873 PMC3602314
Cited by
Sorted by citations
Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies
Bowman, R. L., Busque, L., & Levine, R. L. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.01.011 · Cited by 448 · see citing works
Loss of Dnmt3a Immortalizes Hematopoietic Stem Cells In Vivo
Jeong, M., Park, H. J., Celik, H., Ostrander, E. L., Reyes, J. M., Guzman, A., Rodriguez, B., Lei, Y., Lee, Y., Ding, L., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.025 · Cited by 243 · see citing works
Self-citationA comprehensive transcriptome signature of murine hematopoietic stem cell aging
Flohr Svendsen, A., Yang, D., Kim, K., Lazare, S., Skinder, N., Zwart, E., Mura-Meszaros, A., Ausema, A., von Eyss, B., de Haan, G., et al. (2021) · Blood · doi:10.1182/blood.2020009729 · Cited by 138 · see citing works
Clonal Hematopoiesis: Mechanisms Driving Dominance of Stem Cell Clones
Challen, G., & Goodell, M. A. (2020) · Blood · doi:10.1182/blood.2020006510 · Cited by 131 · see citing works
Self-citationHou, Y., Wei, D., Zhang, Z., Guo, H., Li, S., Zhang, J., Zhang, P., Zhang, L., & Zhao, Y. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111668 · Cited by 100 · see citing works
PRMT7 Preserves Satellite Cell Regenerative Capacity
Blanc, R. S., Vogel, G., Chen, T., Crist, C., & Richard, S. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.022 · Cited by 97 · see citing works
Celik, H., Mallaney, C., Kothari, A., Ostrander, E. L., Eultgen, E., Martens, A., Miller, C. A., Hundal, J., Klco, J. M., & Challen, G. A. (2015) · Blood · doi:10.1182/blood-2014-08-594564 · Cited by 95 · see citing works
Self-citationGlobal DNA methylation remodeling during direct reprogramming of fibroblasts to neurons
Luo, C., Lee, Q. Y., Wapinski, O., Castanon, R., Nery, J. R., Mall, M., Kareta, M. S., Cullen, S. M., Goodell, M. A., Chang, H. Y., et al. (2019) · eLife · doi:10.7554/elife.40197 · Cited by 76 · see citing works
Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation
Evano, B., Gill, D., Hernando-Herraez, I., Comai, G., Stubbs, T. M., Commere, P.-H., Reik, W., & Tajbakhsh, S. (2020) · PLOS Genetics · doi:10.1371/journal.pgen.1009022 · Cited by 40 · see citing works
Tovy, A., Reyes, J. M., Gundry, M. C., Brunetti, L., Lee-Six, H., Petljak, M., Park, H. J., Guzman, A. G., Rosas, C., Jeffries, A. R., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.06.018 · Cited by 30 · see citing works
Self-citation<i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i>
Zhang, C. R., Ostrander, E. L., Kukhar, O., Mallaney, C., Sun, J., Haussler, E., Celik, H., Koh, W. K., King, K. Y., Gontarz, P., et al. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0132 · Cited by 23 · see citing works
Self-citation
- Authors
- Challen, G. A., Sun, D., Mayle, A., Jeong, M., Luo, M., Rodriguez, B., Mallaney, C., Celik, H., Yang, L., Xia, Z., Cullen, S., Berg, J., Zheng, Y., Darlington, G. J., Li, W., & Goodell, M. A.
- Affiliations
- Washington University in St. Louis (US)
- Baylor College of Medicine (US)
- Corresponding author
- Challen, Grant A.
- Goodell, Margaret A.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 15
- Issue
- 3
- Pages
- 350-364
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4163922
- OpenAlex
- W2083536957
- Cited by
- 354
- References
- 2
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 22 · 2023: 24 · 2022: 33 · 2021: 33 · 2020: 46 · 2019: 32 · 2018: 35 · 2017: 26 · 2016: 43 · 2015: 20 · 2014: 4 · 2012: 1
- FWCI
- 21.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas
- National Institutes of Health
- National Institute on Aging (AG036562, RC2AG036562)
- National Heart, Lung, and Blood Institute (T32HL092332)
- National Human Genome Research Institute (R01HG007538)
- National Cancer Institute (CA125123, CA126752, R01CA183252, P30CA125123, P50CA126752)
- National Institute of General Medical Sciences (T32GM008307)
- National Institute of Allergy and Infectious Diseases (T32AI007495, AI07495)
- National Institute of Diabetes and Digestive and Kidney Diseases (K99DK084259, DK084259, DK092883, R56DK092883, T32DK060445, R00DK084259, R01DK092883)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- DNMT3A, DNMT3B, hematopoietic stem cells, de novo methylation, epigenetic regulation, HSC self-renewal, HSC differentiation, conditional gene inactivation, CpG island hypermethylation, β-catenin signaling, Wnt signaling
- MeSH terms
- DNA Methyltransferase 3A, DNA Methyltransferase 3B, Animals, Cell Differentiation, DNA (Cytosine-5-)-Methyltransferases, Hematopoietic Stem Cells, Isoenzymes, Mice, Inbred C57BL, Neoplasms, Apoptosis, Mice, Knockout, Gene Expression Regulation, Developmental, CpG Islands, DNA Methylation, Epigenesis, Genetic, Cell Proliferation, beta Catenin, Gene Regulatory Networks
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
