DNA Methyltransferase 1 Is Essential for and Uniquely Regulates Hematopoietic Stem and Progenitor Cells

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
Cell stem cell (Impact Factor: 22.27). 10/2009; 5(4):442-9. DOI: 10.1016/j.stem.2009.08.016
Source: PubMed

ABSTRACT DNA methylation is essential for development and in diverse biological processes. The DNA methyltransferase Dnmt1 maintains parental cell methylation patterns on daughter DNA strands in mitotic cells; however, the precise role of Dnmt1 in regulation of quiescent adult stem cells is not known. To examine the role of Dnmt1 in adult hematopoietic stem cells (HSCs), we conditionally disrupted Dnmt1 in the hematopoietic system. Defects were observed in Dnmt1-deficient HSC self-renewal, niche retention, and in the ability of Dnmt1-deficient HSCs to give rise to multilineage hematopoiesis. Loss of Dnmt1 also had specific impact on myeloid progenitor cells, causing enhanced cell cycling and inappropriate expression of mature lineage genes. Dnmt1 regulates distinct patterns of methylation and expression of discrete gene families in long-term HSCs and multipotent and lineage-restricted progenitors, suggesting that Dnmt1 differentially controls these populations. These findings establish a unique and critical role for Dnmt1 in the primitive hematopoietic compartment.

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Available from: Jonghwan Kim, Jun 06, 2014
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    • "Previous studies have reported that hematopoietic stem cell self-renewal can be abrogated by conditional gene knockout of DNMT1, while the mature differentiated hematopoietic lineage is not affected (87). DNMT1 is essential for maintenance of the leukemia stem cells of bilinear myeloid-B lymphoid leukemia induced by transduction of c-Myc and Bcl-2 (88). "
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    ABSTRACT: Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents, and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2 or TRDMT1, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination, and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L, are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, it has been shown to function in self-renewal and maintenance of colon cancer stem cells and need to be studied in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anti-cancer targets. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represents a promising approach for the prevention and treatment of many cancers.
    Frontiers in Oncology 05/2014; 4:80. DOI:10.3389/fonc.2014.00080
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    • "DNA methylation has been demonstrated to be required for vertebrate early embryogenesis and can regulate temporal and spatial expression of genes controlling cell fate and differentiation which is a complicated and predetermined developmental program. Moreover, DNA methylation provides necessary direction for the multitude of changes that are required to proceed from a fertilized oocyte to a fully developed adult animal [6,7]. Sperm and eggs carry distinctive epigenetic modifications that are adjusted by reprogramming after fertilization. "
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    ABSTRACT: DNA methylation is a crucial epigenetic modification of the genome which is involved in embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, DNA methylation has been demonstrated to be required for vertebrate early embryogenesis and essential for regulating temporal and spatial expression of genes controlling cell fate and differentiation. Further studies have shown that abnormal DNA methylation is associated with human diseases including the embryonic development diseases. We attempt to study the DNA methylation status of CpG islands in fetus related to fetus growth and development. GeneChip(R) Human Tiling 2.0R Array set is used for analysis of methylated DNA in a whole-genome wide in 8 pairs amniotic fluid and maternal blood DNA samples. We found 1 fetus hypermethylation DNA markers and 4 fetus hypomethylation DNA markers though a Genome-wide analysis. These DNA markers all found to be associated with the critical genes for fetus growth and development (SH2D3C gene, EML3 gene, TRIM71 gene, HOXA3 gene and HOXA5 gene). These genes can be used as a biomarker for association studying of embryonic development, pathological pregnancy and so on. The present study has provided new and fundamental insights into the roles that DNA methylation has in embryonic development and in the pathological pregnancy.
    BMC Medical Genomics 04/2014; 7(1):18. DOI:10.1186/1755-8794-7-18 · 2.87 Impact Factor
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    • "The activity of DNA methyltransferases is also crucial for hematopoiesis. Conditional deletion of the maintenance DNA methyltransferase Dnmt1 in HSCs leads to impaired self-renewal capacity and prevents HSCs from giving rise to hematopoietic progenitors (77). Based on the initial studies, loss of the de novo DNA methyltransferases, Dnmt3a or Dnmt3b alone was thought to have no impact on HSC function (78); by contrast, loss of both together was reported to abolish self-renewal without affecting differentiation capacity (78). "
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