12
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          While aberrant DNA methylation is a characteristic feature of tumor cells, our knowledge of how these DNA methylation patterns are established and maintained is limited. DNA methyltransferases and ten-eleven translocation methylcytosine dioxygenases (TETs) function has been found altered in a variety of cancer types.

          Results

          Here, we report that in T cell acute lymphoblastic leukemia (T-ALL) the MYC oncogene controls the expression of TET1 and TET2 to maintain 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) patterns, which is associated with tumor cell-specific gene expression. We found that cellular senescence and tumor regression upon MYC inactivation in T-ALL was associated with genome-wide changes in 5mC and 5hmC patterns. Correlating with the changes in DNA (hydroxy)methylation, we found that T-ALL overexpress TET1, while suppressing TET2 in a MYC-dependent fashion. Consequently, MYC inactivation led to an inverse expression pattern, decreasing TET1, while increasing TET2 levels. Knockdown of TET1 or ectopic expression of TET2 in T-ALL was associated with genome-wide changes in 5mC and 5hmC enrichment and decreased cell proliferation, suggesting a tumor promoting function of TET1, and a tumor suppressing role for TET2. Among the genes and pathways controlled by TET1, we found ribosomal biogenesis and translational control of protein synthesis highly enriched.

          Conclusions

          Our finding that MYC directly deregulates the expression of TET1 and TET2 in T-ALL provides novel evidence that MYC controls DNA (hydroxy)methylation in a genome-wide fashion. It reveals a coordinated interplay between the components of the DNA (de)methylating machinery that contribute to MYC-driven tumor maintenance, highlighting the potential of specific TET enzymes for therapeutic strategies.

          Electronic supplementary material

          The online version of this article (10.1186/s13072-019-0278-5) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references41

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Role of TET enzymes in DNA methylation, development, and cancer

          Ten eleven translocation (TET) genes, and especially TET2, are frequently mutated in various cancers, but how the TET proteins contribute to the onset and maintenance of these malignancies is largely unknown. In this review, Rasmussen and Helin highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression, and DNA methylation abnormalities are often observed in diseases. The ten eleven translocation (TET) enzymes oxidize 5-methylcytosines (5mCs) and promote locus-specific reversal of DNA methylation. TET genes, and especially TET2 , are frequently mutated in various cancers, but how the TET proteins contribute to prevent the onset and maintenance of these malignancies is largely unknown. Here, we highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. In addition, we discuss some of the key outstanding questions in the field.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            MYC as a regulator of ribosome biogenesis and protein synthesis.

            MYC regulates the transcription of thousands of genes required to coordinate a range of cellular processes, including those essential for proliferation, growth, differentiation, apoptosis and self-renewal. Recently, MYC has also been shown to serve as a direct regulator of ribosome biogenesis. MYC coordinates protein synthesis through the transcriptional control of RNA and protein components of ribosomes, and of gene products required for the processing of ribosomal RNA, the nuclear export of ribosomal subunits and the initiation of mRNA translation. We discuss how the modulation of ribosome biogenesis by MYC may be essential to its physiological functions as well as its pathological role in tumorigenesis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Myc's broad reach.

              The role of the myc gene family in the biology of normal and cancer cells has been intensively studied since the early 1980s. myc genes, responding to diverse external and internal signals, express transcription factors (c-, N-, and L-Myc) that heterodimerize with Max, bind DNA, and modulate expression of a specific set of target genes. Over the last few years, expression profiling, genomic binding studies, and genetic analyses in mammals and Drosophila have led to an expanded view of Myc function. This review is focused on two major aspects of Myc: the nature of the genes and pathways that are targeted by Myc, and the role of Myc in stem cell and cancer biology.
                Bookmark

                Author and article information

                Contributors
                capoole@augusta.edu
                alodh@augusta.edu
                jechoi@augusta.edu
                706-721-0856 , jvanriggelen@augusta.edu
                Journal
                Epigenetics Chromatin
                Epigenetics Chromatin
                Epigenetics & Chromatin
                BioMed Central (London )
                1756-8935
                2 July 2019
                2 July 2019
                2019
                : 12
                : 41
                Affiliations
                [1 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Biochemistry and Molecular Biology, , Augusta University, ; 1410 Laney-Walker Blvd., Augusta, GA 30912 USA
                [2 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Georgia Cancer Center, , Augusta University, ; 1410 Laney-Walker Blvd., Augusta, GA 30912 USA
                Author information
                http://orcid.org/0000-0003-1811-587X
                Article
                278
                10.1186/s13072-019-0278-5
                6604319
                31266538
                d8d0cdd1-f707-44e3-b835-4f04e3d057a4
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 6 March 2019
                : 17 May 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000048, American Cancer Society;
                Award ID: Institutional Research Grant #IRG14-193-01
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Genetics
                myc,tet1,tet2,dna methylation,dna hydroxymethylation,leukemia/lymphoma
                Genetics
                myc, tet1, tet2, dna methylation, dna hydroxymethylation, leukemia/lymphoma

                Comments

                Comment on this article