Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptional regulation of Tet1 during development

ABSTRACT: 5-hydroxymethylcytosine (5hmC) is a recently discovered epigenetic modification that is lost in human cancers. Formation of 5hmC is catalysed by the Ten eleven translocation (TET) proteins that mediate the sequential oxidation of 5-methylcytosine (5mC) to 5hmC, leading to eventual DNA demethylation. Several mechanisms can lead to loss of 5hmC in cancers, including mutations in IDH or TET2 genes. However, little is known about the role of TET proteins and 5hmC in adult cells. Here, we report that TET1 downmodulation is required to permit adult cells to proliferate. TET1 is rapidly downmodulated in proliferating primary cells and in regenerating liver. TET1 silencing accelerates cell cycle progression while its constitutive expression inhibits cell growth. TET1 is a negative regulator of cell proliferation and it is regulated during development in tissue specific manner. These findings enlarge our knowledge on how one epigenetic modification such as the DNA hydroxymethylation mediated by TET1 is a key player on the control of cell proliferation. Examination of 5hmC in MEF at passage 0 and at passage 5.

ORGANISM(S): Mus musculus

SUBMITTER: Francesco Neri

PROVIDER: E-GEOD-57250 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

TET1 is controlled by pluripotency-associated factors in ESCs and downmodulated by PRC2 in differentiated cells and tissues.

Neri Francesco F Incarnato Danny D Krepelova Anna A Dettori Daniela D Rapelli Stefania S Maldotti Mara M Parlato Caterina C Anselmi Francesca F Galvagni Federico F Oliviero Salvatore S

Nucleic acids research 20150429 14

Ten-eleven translocation (Tet) genes encode for a family of hydroxymethylase enzymes involved in regulating DNA methylation dynamics. Tet1 is highly expressed in mouse embryonic stem cells (ESCs) where it plays a critical role the pluripotency maintenance. Tet1 is also involved in cell reprogramming events and in cancer progression. Although the functional role of Tet1 has been largely studied, its regulation is poorly understood. Here we show that Tet1 gene is regulated, both in mouse and human ...[more]

PMID: 25925565

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Project description:DNA methylation of C5-cytosine (5mC) in the mammalian genome is a key epigenetic event that is critical for various cellular processes. However, how the genome-wide 5mC pattern is dynamically regulated remains a fundamental question in epigenetic biology. The TET family of 5mC hydroxylases, which convert 5mC to 5-hydroxymethylcytosine (5hmC), have provided a new potential mechanism for the dynamic regulation of DNA methylation. The extent to which individual Tet family members contribute to the genome-wide 5mC and 5hmC patterns and associated gene network remains largely unknown. Here we report genome-wide mapping of Tet1 and 5hmC in mESCs and reveal a mechanism of action by which Tet1 controls 5hmC and 5mC levels in mESCs. In combination with microarray and mRNA-seq expression profiling, we identify a comprehensive yet intricate gene network influenced by Tet1. We propose a model whereby Tet1 controls DNA methylation both by binding to CpG-rich regions to prevent unwanted DNA methyltransferase activity, and by converting the existing 5mC to 5hmC through its enzymatic activity. This Tet1-mediated antagonism of CpG methylation imparts differential maintenance of DNA methylation status at Tet1 target loci, thereby providing a new regulatory mechanism for establishing the epigenetic landscape of mESCs, which ultimately contributes to mESC differentiation and the onset of embryonic development. To determine the genome-wide distribution of Tet1 and 5hmC in mouse ES cells, as well as identify the gene transcription changes after Tet1 depletion. GSM706669-GSM706671: We used GST pull-down followed by deep sequencing to map the DNA bound by the Tet1 CXXC domain in vitro. We made two mutants that have a single point mutation (Cys574 to Ala or Cys586 to Ala) in the core CXXC domain to ascertain the essential role of the CXXC domain in DNA binding by comparing the sequencing profile of DNA bound by wild type CXXC with the profiles of the CXXC mutants. GSM706672-GSM706673: Tet1 ChIP-seq was performed to identify the genome-wide distribution of Tet1 in mouse ES cells. GSM706674-GSM706679: We performed hydroxymethylated DNA immunoprecipitation (hMeDIP)-seq combined with a shRNA-mediated gene depletion strategy. To identify the loci specific 5hmC regulation by Tet1, we compared the 5hmC genome-wide distributions in control (Luc shRNA) and Tet1-depleted (Tet1 shRNA2863) mouse ES cells. GSM706680-GSM706682: To identify the gene regulation network by Tet1, we compared the gene expression profiles of control (scramble shRNA) and Tet1-depleted (Tet1 shRNA 2863 and Tet1 shRNA 3387) mouse ES cells determined by mRNA-seq.

Dataset Information

Transcriptional regulation of Tet1 during development

Publications

TET1 is controlled by pluripotency-associated factors in ESCs and downmodulated by PRC2 in differentiated cells and tissues.

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