p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity.

Abstract:

:DNA methylation is a key regulator of embryonic stem cell (ESC) biology, dynamically changing between naïve, primed, and differentiated states. The p53 tumor suppressor is a pivotal guardian of genomic stability, but its contributions to epigenetic regulation and stem cell biology are less explored. We report that, in naïve mouse ESCs (mESCs), p53 restricts the expression of the de novo DNA methyltransferases Dnmt3a and Dnmt3b while up-regulating Tet1 and Tet2, which promote DNA demethylation. The DNA methylation imbalance in p53-deficient (p53-/-) mESCs is the result of augmented overall DNA methylation as well as increased methylation landscape heterogeneity. In differentiating p53-/- mESCs, elevated methylation persists, albeit more mildly. Importantly, concomitant with DNA methylation heterogeneity, p53-/- mESCs display increased cellular heterogeneity both in the "naïve" state and upon induced differentiation. This impact of p53 loss on 5-methylcytosine (5mC) heterogeneity was also evident in human ESCs and mouse embryos in vivo. Hence, p53 helps maintain DNA methylation homeostasis and clonal homogeneity, a function that may contribute to its tumor suppressor activity.

journal_name

Genes Dev

journal_title

Genes & development

authors

Tovy A,Spiro A,McCarthy R,Shipony Z,Aylon Y,Allton K,Ainbinder E,Furth N,Tanay A,Barton M,Oren M

doi

10.1101/gad.299198.117

subject

Has Abstract

pub_date

2017-05-15 00:00:00

pages

959-972

issue

10

eissn

0890-9369

issn

1549-5477

pii

gad.299198.117

journal_volume

31

pub_type

杂志文章
  • TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres.

    abstract::Mammalian telomeres are coated by the sequence-specific, DNA-binding protein, TRF1, a negative regulator of telomere length. Previous results showed that ADP-ribosylation of TRF1 by tankyrase 1 released TRF1 from telomeres and promoted telomere elongation. We now show that loss of TRF1 from telomeres results in ubiqui...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1077103

    authors: Chang W,Dynek JN,Smith S

    更新日期:2003-06-01 00:00:00

  • U4/U5/U6 snRNP recognizes the 5' splice site in the absence of U2 snRNP.

    abstract::Using an in vitro system in which a 5' splice site (5'SS) RNA oligo (AAG decreases GUAAGUAdT) is capable of inducing formation of U2/U4/U5/U6 snRNP complex we show that this oligo specifically binds to U4/U5/U6 snRNP and cross-links to U6 snRNA in the absence of U2 snRNP. Moreover, 5'SS RNA oligo bound to U4/U5/U6 snR...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.8.16.1962

    authors: Konforti BB,Konarska MM

    更新日期:1994-08-15 00:00:00

  • Mutation of cancer driver MLL2 results in transcription stress and genome instability.

    abstract::Genome instability is a recurring feature of tumorigenesis. Mutation in MLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence that MLL2 mutation results in genome instability. Mouse cells in which MLL2 gene deletion can be in...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.275453.115

    authors: Kantidakis T,Saponaro M,Mitter R,Horswell S,Kranz A,Boeing S,Aygün O,Kelly GP,Matthews N,Stewart A,Stewart AF,Svejstrup JQ

    更新日期:2016-02-15 00:00:00

  • Transcription elongation factor hSPT5 stimulates mRNA capping.

    abstract::RNA polymerase II nascent transcripts are capped during pausing before elongation. Here we report that hSPT5, the human homolog of yeast elongation factor SPT5, interacts directly with the capping enzyme. hSPT5 stimulated capping enzyme guanylylation and mRNA capping by severalfold. Although RNA 5'-triphosphatase acti...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.13.14.1774

    authors: Wen Y,Shatkin AJ

    更新日期:1999-07-15 00:00:00

  • The SABRE gene is required for normal cell expansion in Arabidopsis.

    abstract::Regulated cell expansion is an important determinant of organ shape in higher plants. The sabre mutation results in abnormal cell expansion in Arabidopsis. There is a shift in the orientation of expansion evident primarily in root cortex cells. The SABRE gene has been cloned and found to encode a novel protein. Reduct...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.9.3.330

    authors: Aeschbacher RA,Hauser MT,Feldmann KA,Benfey PN

    更新日期:1995-02-01 00:00:00

  • SAM68 is required for regulation of Pumilio by the NORAD long noncoding RNA.

    abstract::The number of known long noncoding RNA (lncRNA) functions is rapidly growing, but how those functions are encoded in their sequence and structure remains poorly understood. NORAD (noncoding RNA activated by DNA damage) is a recently characterized, abundant, and highly conserved lncRNA that is required for proper mitot...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.309138.117

    authors: Tichon A,Perry RB,Stojic L,Ulitsky I

    更新日期:2018-01-01 00:00:00

  • Regulation of splicing at an intermediate step in the formation of the spliceosome.

    abstract::In vivo experiments have demonstrated that the ribosomal protein L32 of Saccharomyces cerevisiae brings about the inhibition of splicing of the transcript of its own gene through an RNA structure comprised largely of the first exon. We now show that L32, itself, binds specifically to this RNA. Splicing of the RPL32 tr...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.8.2.211

    authors: Vilardell J,Warner JR

    更新日期:1994-01-01 00:00:00

  • Control of cell division by a retinoblastoma protein homolog in Chlamydomonas.

    abstract::A key pathway that controls both cell division and differentiation in animal cells is mediated by the retinoblastoma (RB) family of tumor suppressors, which gate the passage of cells from G(1) to S and through S phase. The role(s) of the RB pathway in plants are not yet clearly defined, nor has there been any evidence...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.892101

    authors: Umen JG,Goodenough UW

    更新日期:2001-07-01 00:00:00

  • Maternal Eed knockout causes loss of H3K27me3 imprinting and random X inactivation in the extraembryonic cells.

    abstract::Genomic imprinting is essential for mammalian development. Recent studies have revealed that maternal histone H3 Lys27 trimethylation (H3K27me3) can mediate DNA methylation-independent genomic imprinting. However, the regulatory mechanisms and functions of this new imprinting mechanism are largely unknown. Here we dem...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.318675.118

    authors: Inoue A,Chen Z,Yin Q,Zhang Y

    更新日期:2018-12-01 00:00:00

  • Cdk1-Clb4 controls the interaction of astral microtubule plus ends with subdomains of the daughter cell cortex.

    abstract::As in many polarized cells, spindle alignment in yeast is essential and cell cycle regulated. A key step that governs spindle alignment is the selective binding of the Kar9 protein to only one of the two spindle pole bodies (SPBs). It has been suggested that cyclin-dependent kinase Cdc28, in complex with cyclin Clb4, ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.298704

    authors: Maekawa H,Schiebel E

    更新日期:2004-07-15 00:00:00

  • Regulated assembly and disassembly of the yeast telomerase quaternary complex.

    abstract::The enzyme telomerase, which elongates chromosome termini, is a critical factor in determining long-term cellular proliferation and tissue renewal. Hence, even small differences in telomerase levels can have substantial consequences for human health. In budding yeast, telomerase consists of the catalytic Est2 protein ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.246256.114

    authors: Tucey TM,Lundblad V

    更新日期:2014-10-01 00:00:00

  • The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription.

    abstract::When the orphan nuclear receptors TR2 and TR4, the DNA-binding subunits of the DRED repressor complex, are forcibly expressed in erythroid cells of transgenic mice, embryos exhibit a transient mid-gestational anemia as a consequence of a reduction in the number of primitive erythroid cells. GATA-1 mRNA is specifically...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1593307

    authors: Tanabe O,Shen Y,Liu Q,Campbell AD,Kuroha T,Yamamoto M,Engel JD

    更新日期:2007-11-01 00:00:00

  • The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism.

    abstract::Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose depriv...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1985910

    authors: Wellen KE,Lu C,Mancuso A,Lemons JM,Ryczko M,Dennis JW,Rabinowitz JD,Coller HA,Thompson CB

    更新日期:2010-12-15 00:00:00

  • Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells.

    abstract::The transcription factor Ebf1 is an important determinant of early B lymphopoiesis. To gain insight into the functions of Ebf1 at distinct stages of differentiation, we conditionally inactivated Ebf1. We found that Ebf1 is required for the proliferation, survival, and signaling of pro-B cells and peripheral B-cell sub...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.187328.112

    authors: Györy I,Boller S,Nechanitzky R,Mandel E,Pott S,Liu E,Grosschedl R

    更新日期:2012-04-01 00:00:00

  • Nucleocytoplasmic transport: the influenza virus NS1 protein regulates the transport of spliced NS2 mRNA and its precursor NS1 mRNA.

    abstract::Influenza virus unspliced NS1 mRNA, like retroviral pre-mRNAs, is efficiently exported from the nucleus and translated in the cytoplasm of infected cells. With human immunodeficiency virus (HIV), the transport of viral pre-mRNAs is facilitated by the viral Rev protein. We tested the possibility that the influenza viru...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.6.2.255

    authors: Alonso-Caplen FV,Nemeroff ME,Qiu Y,Krug RM

    更新日期:1992-02-01 00:00:00

  • Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.

    abstract::Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras. Here we show that the use of ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.943001

    authors: Jackson EL,Willis N,Mercer K,Bronson RT,Crowley D,Montoya R,Jacks T,Tuveson DA

    更新日期:2001-12-15 00:00:00

  • Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge.

    abstract::The formation of the apical ectodermal ridge (AER) is critical for the distal outgrowth and patterning of the vertebrate limb. Recent work in the chick has demonstrated that interplay between the Wnt and Fgf signaling pathways is essential in the limb mesenchyme and ectoderm in the establishment and perhaps the mainte...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1044903

    authors: Barrow JR,Thomas KR,Boussadia-Zahui O,Moore R,Kemler R,Capecchi MR,McMahon AP

    更新日期:2003-02-01 00:00:00

  • The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1.

    abstract::Apoptosis is an important mechanism to eliminate potentially tumorigenic cells. The tumor suppressor p53 plays a pivotal role in this process. Many tumors harbor mutant p53, but others evade its tumor-suppressive effects by altering the expression of proteins that regulate the p53 pathway. ASPP1 (apoptosis-stimulating...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1954410

    authors: Aylon Y,Ofir-Rosenfeld Y,Yabuta N,Lapi E,Nojima H,Lu X,Oren M

    更新日期:2010-11-01 00:00:00

  • The 65-kD subunit of NF-kappa B is a receptor for I kappa B and a modulator of DNA-binding specificity.

    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

    authors: Urban MB,Baeuerle PA

    更新日期:1990-11-01 00:00:00

  • Dual mechanisms prevent premature chromosome segregation during meiosis.

    abstract::In meiosis I, homologous chromosomes pair and then attach to the spindle so that the homologs can be pulled apart at anaphase I. The segregation of homologs before pairing would be catastrophic. We describe two mechanisms that prevent this. First, in early meiosis, Ipl1, the budding yeast homolog of the mammalian Auro...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.227454.113

    authors: Kim S,Meyer R,Chuong H,Dawson DS

    更新日期:2013-10-01 00:00:00

  • JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias.

    abstract::Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.307504.117

    authors: Kim SK,Knight DA,Jones LR,Vervoort S,Ng AP,Seymour JF,Bradner JE,Waibel M,Kats L,Johnstone RW

    更新日期:2018-06-01 00:00:00

  • Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis.

    abstract::Treatment with retinoic acid (RA) is known to produce complex teratogenic effects in vertebrates, and its presence in the developing embryo as an endogenous substance has led to the suggestion that RA might be a natural morphogenetic agent. Although our understanding of the molecular mechanism of RA action has improve...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.5.8.1333

    authors: Rossant J,Zirngibl R,Cado D,Shago M,Giguère V

    更新日期:1991-08-01 00:00:00

  • Max deletion destabilizes MYC protein and abrogates Eµ-Myc lymphomagenesis.

    abstract::Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell-specific deletion of Max has a modest effect on B-cell development but completely abrogates Eµ-Myc-driven lymphomagenesis. While Max loss affects only a few hund...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.325878.119

    authors: Mathsyaraja H,Freie B,Cheng PF,Babaeva E,Catchpole JT,Janssens D,Henikoff S,Eisenman RN

    更新日期:2019-09-01 00:00:00

  • Psidin, a conserved protein that regulates protrusion dynamics and cell migration.

    abstract::Dynamic assembly and disassembly of actin filaments is a major driving force for cell movements. Border cells in the Drosophila ovary provide a simple and genetically tractable model to study the mechanisms regulating cell migration. To identify new genes that regulate cell movement in vivo, we screened lethal mutatio...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.2028611

    authors: Kim JH,Cho A,Yin H,Schafer DA,Mouneimne G,Simpson KJ,Nguyen KV,Brugge JS,Montell DJ

    更新日期:2011-04-01 00:00:00

  • canoe encodes a novel protein containing a GLGF/DHR motif and functions with Notch and scabrous in common developmental pathways in Drosophila.

    abstract::The canoemisty1 (cnomis1) mutation was isolated by virtue of its severe rough eye phenotype from approximately 500 fly lines, each harboring a single autosomal insertion of a P element (Bm delta w). Excision of the P element generated a lethal, null allele, cnomis10, together with many revertants with normal eye morph...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.9.5.612

    authors: Miyamoto H,Nihonmatsu I,Kondo S,Ueda R,Togashi S,Hirata K,Ikegami Y,Yamamoto D

    更新日期:1995-03-01 00:00:00

  • Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum.

    abstract::Medulloblastomas are among the most common malignancies in childhood, and they are associated with substantial mortality and morbidity. The molecular pathogenesis as well as the ontogeny of these neoplasms is still poorly understood. We have generated a mouse model for medulloblastoma by Cre-LoxP-mediated inactivation...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:

    authors: Marino S,Vooijs M,van Der Gulden H,Jonkers J,Berns A

    更新日期:2000-04-15 00:00:00

  • β-Actin mRNA compartmentalization enhances focal adhesion stability and directs cell migration.

    abstract::Directed cell motility is at the basis of biological phenomena such as development, wound healing, and metastasis. It has been shown that substrate attachments mediate motility by coupling the cell's cytoskeleton with force generation. However, it has been unclear how the persistence of cell directionality is facilita...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.190413.112

    authors: Katz ZB,Wells AL,Park HY,Wu B,Shenoy SM,Singer RH

    更新日期:2012-09-01 00:00:00

  • Skewing X chromosome choice by modulating sense transcription across the Xist locus.

    abstract::The X-inactive-specific transcript (Xist) locus is a cis-acting switch that regulates X chromosome inactivation in mammals. Over recent years an important goal has been to understand how Xist is regulated at the initiation of X inactivation. Here we report the analysis of a series of targeted mutations at the 5' end o...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.271203

    authors: Nesterova TB,Johnston CM,Appanah R,Newall AE,Godwin J,Alexiou M,Brockdorff N

    更新日期:2003-09-01 00:00:00

  • Abro1 maintains genome stability and limits replication stress by protecting replication fork stability.

    abstract::Protection of the stalled replication fork is crucial for responding to replication stress and minimizing its impact on chromosome instability, thus preventing diseases, including cancer. We found a new component, Abro1, in the protection of stalled replication fork integrity. Abro1 deficiency results in increased chr...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.299172.117

    authors: Xu S,Wu X,Wu L,Castillo A,Liu J,Atkinson E,Paul A,Su D,Schlacher K,Komatsu Y,You MJ,Wang B

    更新日期:2017-07-15 00:00:00

  • Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication.

    abstract::All viruses require cellular ribosomes to translate their mRNAs. Viruses producing methyl-7 (m⁷) GTP-capped mRNAs, like Herpes Simplex Virus-1 (HSV-1), stimulate cap-dependent translation by activating mTORC1 to inhibit the translational repressor 4E-binding protein 1 (4E-BP1). Here, we establish that the HSV-1 kinase...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1978310

    authors: Chuluunbaatar U,Roller R,Feldman ME,Brown S,Shokat KM,Mohr I

    更新日期:2010-12-01 00:00:00