Abstract:
:DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles and hallmarks of human AML1-ETO-induced AML. Using this model, we show that the primary effect of Tet2 loss in preleukemic hematopoietic cells is progressive and widespread DNA hypermethylation affecting up to 25% of active enhancer elements. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner but increases relative to population doublings. We confirmed this specific enhancer hypermethylation phenotype in human AML patients with TET2 mutations. Analysis of immediate gene expression changes reveals rapid deregulation of a large number of genes implicated in tumorigenesis, including many down-regulated tumor suppressor genes. Hence, we propose that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation and that it is the combined silencing of several tumor suppressor genes in TET2 mutated hematopoietic cells that contributes to increased stem cell proliferation and leukemogenesis.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Rasmussen KD,Jia G,Johansen JV,Pedersen MT,Rapin N,Bagger FO,Porse BT,Bernard OA,Christensen J,Helin Kdoi
10.1101/gad.260174.115subject
Has Abstractpub_date
2015-05-01 00:00:00pages
910-22issue
9eissn
0890-9369issn
1549-5477pii
gad.260174.115journal_volume
29pub_type
杂志文章abstract::Pre-mRNA processing is coupled with transcription. It is still unclear if the transcription machinery can also directly affect the cytoplasmic fate of a transcript, such as its intracellular localization. In yeast, the RNA-binding protein She2p binds several mRNAs and targets them for localization at the bud. Here we ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1937510
更新日期:2010-09-01 00:00:00
abstract::Eph receptors and ephrin ligands are key players in many developmental processes including embryo patterning, angiogenesis, and axon guidance. Eph/ephrin interactions lead to the generation of a bidirectional signal, in which both the Eph receptors and the ephrins activate downstream signaling cascades simultaneously....
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1171704
更新日期:2004-03-01 00:00:00
abstract::The Hox gene products are transcription factors involved in specifying regional identity along the anteroposterior body axis. In the mouse, several single mutants for Hox genes show variably penetrant, partial homeotic transformations of vertebrae at their anterior limits of expression, suggesting that compound Hox mu...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.9.13.1667
更新日期:1995-07-01 00:00:00
abstract::Epigenetic modifications of chromatin play an important role in the regulation of gene expression. KMT4/Dot1 is a conserved histone methyltransferase capable of methylating chromatin on Lys79 of histone H3 (H3K79). Here we report the identification of a multisubunit Dot1 complex (DotCom), which includes several of the...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1898410
更新日期:2010-03-15 00:00:00
abstract::Two retrovirus promoter trap vectors (U3His and U3Neo) have been used to disrupt genes expressed in totipotent murine embryonal stem (ES) cells. Selection in L-histidinol or G418 produced clones in which the coding sequences for histidinol-dehydrogenase or neomycin-phosphotransferase were fused to sequences in or near...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.6.6.919
更新日期:1992-06-01 00:00:00
abstract::Cell cycle transitions are often accompanied by the degradation of regulatory molecules. Targeting proteins to the proteasome for degradation is accomplished by the covalent addition of ubiquitin chains. The specificity of this pathway is largely dictated by a set of enzymes called ubiquitin ligases (or E3s). The anap...
journal_title:Genes & development
pub_type: 杂志文章,评审
doi:10.1101/gad.1478306
更新日期:2006-11-15 00:00:00
abstract::C-factor, the product of the csgA gene, is a cell-surface associated short-range intercellular signaling protein in Myxococcus xanthus. C-factor is required for at least four responses during starvation-induced fruiting body morphogenesis: rippling, aggregation, sporulation, and full expression of the csgA gene, all o...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.6.740
更新日期:1996-03-15 00:00:00
abstract::Eukaryotic genomes encode large families of deubiquitinating enzymes (DUBs). Genetic data suggest that Fat facets (Faf), a Drosophila DUB essential for patterning the compound eye, might have a novel regulatory function; Faf might reverse the ubiquitination of a specific substrate, thereby preventing proteasomal degra...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.961502
更新日期:2002-02-01 00:00:00
abstract::Innate immunity against pathogen infection is an evolutionarily conserved process among multicellular organisms. Arabidopsis SNC1 encodes a Resistance protein that combines attributes of multiple mammalian pattern recognition receptors. Utilizing snc1 as an autoimmune model, we identified a discrete protein complex co...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1559607
更新日期:2007-06-15 00:00:00
abstract::P-element transformants of a single rRNA gene (rDNA) were used to investigate the relationship between the organization of the nucleolus organizer (NO) and rDNA function in Drosophila melanogaster. In situ hybridization to rRNA in polytene nuclei of salivary glands demonstrated that an rRNA gene can be transcribed at ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.2.12b.1745
更新日期:1988-12-01 00:00:00
abstract::Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. I...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.340133.120
更新日期:2020-09-01 00:00:00
abstract::A recent study has shown that the dimeric form of the 50-kD DNA-binding subunit of the NF-kappa B transcription factor is commonly associated with two molecules of a 65-kD protein (p65) and that p65 appears to be required for inactivation of the p50 dimer by the inhibitory subunit I kappa B. Here, we provide evidence ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.4.11.1975
更新日期:1990-11-01 00:00:00
abstract::Recombination catalyzed by the Flp site-specific recombinase involves breakage and joining of four DNA strands between two target substrates. The reaction is carried out in two steps of pairwise strand exchanges by a DNA-protein assembly in which four Flp monomers act cooperatively to execute strand cleavage and joini...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.11.18.2438
更新日期:1997-09-15 00:00:00
abstract::We showed previously that the MAP kinase ERK2 is essential for aggregation. erk2 null cells lack cAMP stimulation of adenylyl cyclase and thus cannot relay the cAMP chemotactic signal, although the cells chemotax to cAMP (Segall et al. 1995). In this paper we have examined the role of ERK2 in controlling developmental...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.1.118
更新日期:1996-01-01 00:00:00
abstract::Myxococcus xanthus development requires CsgA, a member of the short-chain alcohol dehydrogenase (SCAD) family of proteins. We show that CsgA and SocA, a protein that can replace CsgA function in vivo, oxidize the 2'-OH glycerol moiety on cardiolipin and phosphatidylglycerol to produce diacylglycerol (DAG), dihydroxyac...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.268482.115
更新日期:2015-09-15 00:00:00
abstract::All multisubunit DNA-dependent RNA polymerases (RNAP) are zinc metalloenzymes, and at least two zinc atoms are present per enzyme molecule. RNAP residues involved in zinc binding and the functional role of zinc ions in the transcription mechanism or RNAP structure are unknown. Here, we locate four cysteine residues in...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.13.18.2439
更新日期:1999-09-15 00:00:00
abstract::Alternative splicing factor/splicing factor 2 (ASF/SF2) is the prototype of a family of nuclear proteins highly conserved throughout metazoa, the SR (serine/arginine) proteins. Based largely on in vitro studies, SR proteins have been suggested to play important roles in constitutive and alternative splicing of pre-mRN...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.20.2588
更新日期:1996-10-15 00:00:00
abstract::The Neurospora crassa clock-controlled gene (ccg-2) is transcriptionally activated by the circadian clock in a time-of-day-specific manner. Transcript and sequence analyses of ccg-2 reveal that the predicted Ccg-2 polypeptide bears significant similarity to a class of low-molecular-weight, cysteine-rich, hydrophobic p...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.6.12a.2382
更新日期:1992-12-01 00:00:00
abstract::We describe here a new murine homeo box gene, denoted Hlx, which is expressed within specific hematopoietic lineages. The cDNA sequence indicates that Hlx differs markedly from known vertebrate homeo box genes, and linkage analysis of an interspecific murine backcross showed that it resides at a novel homeo box locus ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.5.4.509
更新日期:1991-04-01 00:00:00
abstract::Dendrite arborization patterns are critical determinants of neuronal function. To explore the basis of transcriptional regulation in dendrite pattern formation, we used RNA interference (RNAi) to screen 730 transcriptional regulators and identified 78 genes involved in patterning the stereotyped dendritic arbors of cl...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1391006
更新日期:2006-04-01 00:00:00
abstract::Human ELAV proteins are implicated in cell growth and differentiation via regulation of mRNA expression in the cytoplasm. In human embryonic teratocarcinoma (hNT2) cells transfected with the human neuronal ELAV-like protein, Hel-N1, neurites formed, yet cells were not terminally differentiated. Cells in which neurite ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.13.4.449
更新日期:1999-02-15 00:00:00
abstract::Dosage compensation is a process required to balance the expression of X-linked genes between males and females. In Drosophila this is achieved by targeting the dosage compensation complex or the male-specific lethal (MSL) complex to the male X chromosome. In order to study the mechanism of targeting, we have studied ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.430807
更新日期:2007-08-15 00:00:00
abstract::Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SM...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.339978.120
更新日期:2020-10-01 00:00:00
abstract::Ribonucleotide reductase activity is essential for progression through the cell cycle, catalyzing the rate-limiting step for the production of deoxyribonucleotides needed for DNA synthesis. The enzymatic activity of the enzyme fluctuates in the cell cycle with an activity maximum in S phase. We have identified and cha...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.4.5.740
更新日期:1990-05-01 00:00:00
abstract::Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.286112.116
更新日期:2016-10-01 00:00:00
abstract::Although branchpoint recognition is an essential component of intron excision during the RNA splicing process, the branchpoint itself is frequently assumed to be a basal, rather than regulatory, sequence feature. However, this assumption has not been systematically tested due to the technical difficulty of identifying...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.312058.118
更新日期:2018-04-01 00:00:00
abstract::Kinase suppressor of Ras (KSR) is a recently identified component of Ras-dependent signaling pathways. In this report, we show that murine KSR1 (mKSR1) cooperates with activated Ras to promote Xenopus oocyte maturation and cellular transformation and provide evidence that this cooperation occurs by accelerating mitoge...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.21.2684
更新日期:1996-11-01 00:00:00
abstract::The dihydrofolate reductase (DHFR) and 2BE2121 genes in the Chinese hamster are convergently transcribed in late G1 and ea ly S phase, and bracket an early-firing origin of replication that consists of a 55-kb zone of potential initiation sites. To test whether transcription through the DHFR gene is required to activa...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1171404
更新日期:2004-02-15 00:00:00
abstract::The amyloid precursor protein (APP) has garnered considerable attention due to its genetic links to Alzheimer's disease. Death receptor 6 (DR6) was recently shown to bind APP via the protein extracellular regions, stimulate axonal pruning, and inhibit synapse formation. Here, we report the crystal structure of the DR6...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.257675.114
更新日期:2015-04-15 00:00:00
abstract::Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%-5%. The cancer's lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biol...
journal_title:Genes & development
pub_type: 杂志文章,评审
doi:10.1101/gad.1415606
更新日期:2006-05-15 00:00:00