Remethylation of Dnmt3a −/− hematopoietic cells is associated with partial correction of gene dysregulation and reduced myeloid skewing
| Autor: | Mieke Hoock, Catrina Fronick, Gue Su Chang, Angela M. Verdoni, David H. Spencer, Elizabeth R. Leight, Robert S. Fulton, Celia V. Bangert, Christopher A. Miller, Meryl K. Brune, Nichole M. Helton, Timothy J. Ley, Amanda Smith, Daniel R. George, David Y. Chen, Sai Mukund Ramakrishnan, Shamika Ketkar, Allegra A. Petti |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Mutation Multidisciplinary Myeloid Myeloid leukemia Biology medicine.disease_cause 3. Good health 03 medical and health sciences Haematopoiesis 0302 clinical medicine medicine.anatomical_structure Differentially methylated regions 030220 oncology & carcinogenesis embryonic structures DNA methylation Cancer research medicine Bone marrow 030304 developmental biology DNA hypomethylation |
| Zdroj: | Proceedings of the National Academy of Sciences. 117:3123-3134 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1918611117 |
| Popis: | Mutations in the DNA methyltransferase 3A ( DNMT3A ) gene are the most common cause of age-related clonal hematopoiesis (ARCH) in older individuals, and are among the most common initiating events for acute myeloid leukemia (AML). The most frequent DNMT3A mutation in AML patients (R882H) encodes a dominant-negative protein that reduces methyltransferase activity by ∼80% in cells with heterozygous mutations, causing a focal, canonical DNA hypomethylation phenotype; this phenotype is partially recapitulated in murine Dnmt3a −/− bone marrow cells. To determine whether the hypomethylation phenotype of Dnmt3a −/− hematopoietic cells is reversible, we developed an inducible transgene to restore expression of DNMT3A in transplanted bone marrow cells from Dnmt3a −/− mice. Partial remethylation was detected within 1 wk, but near-complete remethylation required 6 mo. Remethylation was accurate, dynamic, and highly ordered, suggesting that differentially methylated regions have unique properties that may be relevant for their functions. Importantly, 22 wk of DNMT3A addback partially corrected dysregulated gene expression, and mitigated the expansion of myeloid cells. These data show that restoring DNMT3A expression can alter the epigenetic “state” created by loss of Dnmt3a activity; this genetic proof-of-concept experiment suggests that this approach could be relevant for patients with ARCH or AML caused by loss-of-function DNMT3A mutations. |
| Databáze: | OpenAIRE |
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