Abstract:
:DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.
journal_name
Naturejournal_title
Natureauthors
Guo X,Wang L,Li J,Ding Z,Xiao J,Yin X,He S,Shi P,Dong L,Li G,Tian C,Wang J,Cong Y,Xu Ydoi
10.1038/nature13899subject
Has Abstractpub_date
2015-01-29 00:00:00pages
640-4issue
7536eissn
0028-0836issn
1476-4687pii
nature13899journal_volume
517pub_type
杂志文章相关文献
NATURE文献大全abstract::Subcutaneous (s.c.) administration of Arg-vasopressin (AVP) prolongs retention of a learned behaviour and elevates arterial blood pressure. Intracerebroventricular (i.c.v.) injection of a thousandfold lower dose of AVP than needed with s.c. injection produces the same behavioural effect, suggesting that AVP acts on th...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/301608a0
更新日期:1983-02-17 00:00:00
abstract::The factors determining disease severity in malaria are complex and include host polymorphisms, acquired immunity and parasite virulence. Studies in Africa have shown that severe malaria is associated with the ability of erythrocytes infected with the parasite Plasmodium falciparum to bind uninfected erythrocytes and ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/40888
更新日期:1997-07-17 00:00:00
abstract::Brosnan and de Waal report that capuchin monkeys show evidence of a sense of fairness or 'inequity aversion' because they rejected a less preferred reward when they saw a partner monkey receive a preferred reward for the same task. However, this does not show that monkeys are averse to inequity, only that they reject ...
journal_title:Nature
pub_type: 评论,杂志文章
doi:10.1038/428140a
更新日期:2004-03-11 00:00:00
abstract::How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo. ANGPTLs also have importan...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature11095
更新日期:2012-05-30 00:00:00
abstract::An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title:Nature
pub_type: 已发布勘误
doi:10.1038/s41586-020-2544-x
更新日期:2020-08-01 00:00:00
abstract::Quantum information science involves the storage, manipulation and communication of information encoded in quantum systems, where the phenomena of superposition and entanglement can provide enhancements over what is possible classically. Large-scale quantum information processors require stable and addressable quantum...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature06118
更新日期:2007-09-06 00:00:00
abstract::Y chromosomes underlie sex determination in mammals, but their repeat-rich nature has hampered sequencing and associated evolutionary studies. Here we trace Y evolution across 15 representative mammals on the basis of high-throughput genome and transcriptome sequencing. We uncover three independent sex chromosome orig...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature13151
更新日期:2014-04-24 00:00:00
abstract::Molecular-scale manipulation of electronic and ionic charge accumulation in materials is the backbone of electrochemical energy storage1-4. Layered van der Waals (vdW) crystals are a diverse family of materials into which mobile ions can electrochemically intercalate into the interlamellar gaps of the host atomic latt...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-018-0205-0
更新日期:2018-06-01 00:00:00
abstract::Trophic control over the expression and membrane distribution of voltage-dependent ion channels is one of the principal organizing events underlying the maturation of excitable cells. The myelin sheath is a major structural determinant of regional ion channel topography in central axons, but the exact molecular signal...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/352431a0
更新日期:1991-08-01 00:00:00
abstract::Several hormones and neurotransmitters raise the cytosolic free Ca2+ concentration by stimulating the influx of Ca2+ and/or by mobilizing stored Ca2+. However, the link between the agonist receptor on the cell surface and the organelle(s) from which Ca2+ is mobilized is unknown. One feature of the agonists that increa...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/309562a0
更新日期:1984-06-07 00:00:00
abstract::Dehydration embrittlement has been proposed to explain both intermediate- and deep-focus earthquakes in subduction zones. Because such earthquakes primarily occur at shallow depths or within the core of the subducting plate, dehydration at relatively low temperatures has been emphasized. However, recent careful reloca...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature02475
更新日期:2004-04-08 00:00:00
abstract::The mechanism by which insulin regulates cellular metabolism remains unknown although indirect evidence suggests that alterations in intracellular calcium are important. More specifically, it has been proposed that insulin triggers an increase in intracellular calcium which is responsible for the subsequent modificati...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/281495a0
更新日期:1979-10-11 00:00:00
abstract::CDKN2A (INK4a/ARF) is frequently disrupted in various types of human cancer, and germline mutations of this locus can confer susceptibility to melanoma and other tumours. However, because CDKN2A encodes two distinct cell cycle inhibitory proteins, p16INK4a and p14ARF (p19Arf in mice), the mechanism of tumour suppressi...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35092584
更新日期:2001-09-06 00:00:00
abstract::The T-cell receptor has been studied intensely over the past 10 years in an effort to understand the molecular basis for major histocompatibility complex (MHC) restricted antigen recognition. The use of anti-receptor monoclonal antibodies to isolate and characterize the receptor from human and murine T-cell clones has...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/312771a0
更新日期:1984-12-20 00:00:00
abstract::Introduced in its contemporary form in 1946 (ref. 1), but with roots that go back to the eighteenth century, the gravity law is the prevailing framework with which to predict population movement, cargo shipping volume and inter-city phone calls, as well as bilateral trade flows between nations. Despite its widespread ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10856
更新日期:2012-02-26 00:00:00
abstract::Overexploitation of renewable resources today has a high cost on the welfare of future generations. Unlike in other public goods games, however, future generations cannot reciprocate actions made today. What mechanisms can maintain cooperation with the future? To answer this question, we devise a new experimental para...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature13530
更新日期:2014-07-10 00:00:00
abstract::In Fig. 3c of this Letter, the the effects of CRISPR-Cas9-mediated deletion of NR3C1, TXNIP and CNR2 in patient-derived B-lineage leukaemia cells were shown. For curves depicting NR3C1 (left graph), data s for TXNIP (middle graph) were inadvertently plotted. This figure has been corrected online, and the original Fig....
journal_title:Nature
pub_type: 杂志文章,已发布勘误
doi:10.1038/s41586-018-0164-5
更新日期:2018-06-01 00:00:00
abstract::The cortex organizes sensory information to enable discrimination and generalization1-4. As systematic representations of chemical odour space have not yet been described in the olfactory cortex, it remains unclear how odour relationships are encoded to place chemically distinct but similar odours, such as lemon and o...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-2451-1
更新日期:2020-07-01 00:00:00
abstract::Planetary formation theories suggest that the giant planets formed on circular and coplanar orbits. The eccentricities of Jupiter, Saturn and Uranus, however, reach values of 6 per cent, 9 per cent and 8 per cent, respectively. In addition, the inclinations of the orbital planes of Saturn, Uranus and Neptune take maxi...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature03539
更新日期:2005-05-26 00:00:00
abstract::Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated retroviral sequences that affect genome regulation and cell physiology throughout their RNA-centred life cycle1. Failure to repress ERVs is associated with cancer, infertility, senescence and neurodegenerative diseases2,3. Here, using an...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-03135-1
更新日期:2021-01-13 00:00:00
abstract::Templates are widely used to arrange molecular components so they can be covalently linked into complex molecules that are not readily accessible by classical synthetic methods. Nature uses sophisticated templates such as the ribosome, whereas chemists use simple ions or small molecules. But as we tackle the synthesis...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09683
更新日期:2011-01-06 00:00:00
abstract::Accurate chromosome segregation requires timely dissolution of chromosome cohesion after chromosomes are properly attached to the mitotic spindle. Separase is absolutely essential for cohesion dissolution in organisms from yeast to man. It cleaves the kleisin subunit of cohesin and opens the cohesin ring to allow chro...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature17402
更新日期:2016-04-07 00:00:00
abstract::Folding of two monomeric enzymes mediated by groE has been reconstituted in vitro. The groEL protein stabilizes the polypeptides in a conformation resembling the 'molten globule' state. Mg-ATP and groES then promote the acquisition of ordered tertiary structure at the surface of groEL. Folding requires the hydrolysis ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/352036a0
更新日期:1991-07-04 00:00:00
abstract::A conserved heterotrimeric membrane protein complex, the Sec61 or SecY complex, forms a protein-conducting channel, allowing polypeptides to be transferred across or integrated into membranes. We report the crystal structure of the complex from Methanococcus jannaschii at a resolution of 3.2 A. The structure suggests ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature02218
更新日期:2004-01-01 00:00:00
abstract::Nerve growth factor (NGF) activity was not detected by bioassay in irides killed immediately after excision but NGF appeared within 24 h in living irides placed in culture or grafted to a host eye. Furthermore, sensory and, although less effective, sympathetic denervation of irides in situ led within 10 days to the ap...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/286025a0
更新日期:1980-07-03 00:00:00
abstract::Photosynthetic dinoflagellates are important aquatic primary producers and notorious causes of toxic 'red tides'. Typical dinoflagellate chloroplasts differ from all other plastids in having a combination of three envelope membranes and peridinin-chlorophyll a/c light-harvesting pigments. Despite evidence of a dinofla...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/22099
更新日期:1999-07-08 00:00:00
abstract::Since its discovery in 1989, efforts to grow clinical isolates of the hepatitis C virus (HCV) in cell culture have met with limited success. Only the JFH-1 isolate has the capacity to replicate efficiently in cultured hepatoma cells without cell culture-adaptive mutations. We hypothesized that cultured cells lack one ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14899
更新日期:2015-08-27 00:00:00
abstract::During endocytosis, clathrin and the clathrin adaptor protein AP-2, assisted by a variety of accessory factors, help to generate an invaginated bud at the cell membrane. One of these factors is Eps15, a clathrin-coat-associated protein that binds the alpha-adaptin subunit of AP-2. Here we investigate the function of E...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/29555
更新日期:1998-08-20 00:00:00
abstract::The cellular oncogene c-Ki-ras is amplified 30- to 60-fold in cells of the mouse adrenocortical tumour Y1. The amplified oncogene is located in double minute chromosomes and in a homogeneously staining chromosomal region, common karyotypical anomalies of tumour cells. The amounts of c-Ki-ras specific mRNA and of the p...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/303497a0
更新日期:1983-06-09 00:00:00
abstract::p97 is a 97,000 molecular weight cell-surface glycoprotein, which is present in human melanomas but in only trace amounts in normal adult tissues. Amino acid sequence and iron binding studies have shown that p97 is structurally and functionally related to transferrin. Reports that the genes for the transferrin recepto...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/303070a0
更新日期:1983-05-05 00:00:00