Abstract:
:Gains and losses in DNA methylation are prominent features of mammalian cell types. To gain insight into the mechanisms that promote shifts in DNA methylation and contribute to changes in cell fate, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. We discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and are distinct from CpG islands and shores. About half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (HSCs). Canyon borders are demarked by 5-hydroxymethylcytosine and become eroded in the absence of DNA methyltransferase 3a (Dnmt3a). Genes dysregulated in human leukemias are enriched for canyon-associated genes. The new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Jeong M,Sun D,Luo M,Huang Y,Challen GA,Rodriguez B,Zhang X,Chavez L,Wang H,Hannah R,Kim SB,Yang L,Ko M,Chen R,Göttgens B,Lee JS,Gunaratne P,Godley LA,Darlington GJ,Rao A,Li W,Goodell MAdoi
10.1038/ng.2836subject
Has Abstractpub_date
2014-01-01 00:00:00pages
17-23issue
1eissn
1061-4036issn
1546-1718pii
ng.2836journal_volume
46pub_type
杂志文章相关文献
NATURE GENETICS文献大全abstract::Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe. High mutability and the likelihood of cancer can be caused...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1172
更新日期:2003-07-01 00:00:00
abstract::The promyelocytic leukaemia zinc finger (Plzf) protein (encoded by the gene Zfp145) belongs to the POZ/zinc-finger family of transcription factors. Here we generate Zfp145-/- mice and show that Plzf is essential for patterning of the limb and axial skeleton. Plzf inactivation results in patterning defects affecting al...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/76014
更新日期:2000-06-01 00:00:00
abstract::Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precanc...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.2796
更新日期:2013-12-01 00:00:00
abstract::Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we obs...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3488
更新日期:2016-03-01 00:00:00
abstract::Three hundred million individuals are at risk of infection by schistosomes and around 200,000 die each year of this disease. Severe clinical disease in schistosomiasis is often the consequence of heavy infection which, in several endemic areas, are determined largely by the susceptibility/resistance of individuals. Pr...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1096-181
更新日期:1996-10-01 00:00:00
abstract::The mammalian homeobox transcription factor CDX2 has key roles in intestinal development and differentiation. Heterozygous Cdx2 mice develop one or two benign hamartomas in the proximal colon, whereas heterozygous Apc(Delta716) mice develop numerous adenomatous polyps, mostly in the small intestine. Here we show that ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1265
更新日期:2003-12-01 00:00:00
abstract::Age-related hearing loss (AHL) in common inbred mouse strains is a genetically complex quantitative trait. We found a synonymous single-nucleotide polymorphism in exon 7 of Cdh23 that shows significant association with AHL and the deafness modifier mdfw (modifer of deafwaddler). The hypomorphic Cdh23(753A) allele caus...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1226
更新日期:2003-09-01 00:00:00
abstract::No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induc...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3380
更新日期:2015-10-01 00:00:00
abstract::Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding a...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1842
更新日期:2006-08-01 00:00:00
abstract::Studying consanguineous families with Ghosal hematodiaphyseal dysplasia syndrome (GHDD), a disorder of increased bone density, we identified mutations in TBXAS1, which encodes thromboxane synthase (TXAS). TXAS, an enzyme of the arachidonic acid cascade, produces thromboxane A(2) (TXA(2)). Platelets from subjects with ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.2007.66
更新日期:2008-03-01 00:00:00
abstract::Epileptic disorders affect about 20-40 million people worldwide, and 40% of these are idiopathic generalized epilepsies (IGEs; ref. 1). Most of the IGEs that are inherited are complex, multigenic diseases. To address basic mechanisms for epilepsies, we have focused on one well-defined class of IGEs with an autosomal-d...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng0198-53
更新日期:1998-01-01 00:00:00
abstract::Large-scale mutagenesis of the mouse genome is an essential task associated with the Human Genome Project. The two opposing schools of direct and reverse genetics have demonstrated comparable advantages, and yet large numbers of mutant lines have mostly been the prerogative of direct genetics. An improved gene-trappin...
journal_title:Nature genetics
pub_type: 评论,新闻
doi:10.1038/90017
更新日期:2001-07-01 00:00:00
abstract::Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.2503
更新日期:2013-02-01 00:00:00
abstract::Systemic lupus erythematosus (SLE) is a highly prevalent human autoimmune diseases that causes progressive glomerulonephritis, arthritis and an erythematoid rash. Mice deficient in deoxyribonuclease I (Dnase1) develop an SLE-like syndrome. Here we describe two patients with a heterozygous nonsense mutation in exon 2 o...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/91070
更新日期:2001-08-01 00:00:00
abstract::Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-kappaB pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.518
更新日期:2010-02-01 00:00:00
abstract::Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT inte...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1790
更新日期:2006-06-01 00:00:00
abstract::Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These find...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3040
更新日期:2014-08-01 00:00:00
abstract::Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-pron...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/s41588-018-0285-7
更新日期:2019-01-01 00:00:00
abstract::Joubert syndrome-related disorders (JSRD) are a group of syndromes sharing the neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'. We identified mutations in the CEP290 gene in five families with variable neurological, retinal and renal mani...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1805
更新日期:2006-06-01 00:00:00
abstract::Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3465
更新日期:2016-01-01 00:00:00
abstract::Recent studies of human oocytes have demonstrated an enrichment for distal exchanges among meiosis I (MI) nondisjunction events and for proximal exchanges among meiosis II (MII) events. Our characterization of 103 cases of spontaneous X chromosome nondisjunction in Drosophila oocytes strongly parallels these observati...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1296-406
更新日期:1996-12-01 00:00:00
abstract::Antimalarial drugs impose strong selective pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome; screening for genes under selection may suggest potential drug or immune targets. Genome-wide association studies (GWAS) of parasite traits have been hampered by the lack of ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.528
更新日期:2010-03-01 00:00:00
abstract::Atopic or immunoglobulin E (IgE)-mediated diseases include the common disorders of asthma, atopic dermatitis and allergic rhinitis. Chromosome 13q14 shows consistent linkage to atopy and the total serum IgE concentration. We previously identified association between total serum IgE levels and a novel 13q14 microsatell...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1166
更新日期:2003-06-01 00:00:00
abstract::UV-sensitive syndrome (UV(S)S) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma. Despite mild clinical features, cells from individuals with UV(S)S, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER), ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.2229
更新日期:2012-05-01 00:00:00
abstract::Human-derived tumor models are becoming popular in the context of personalized medicine, but a new study shows that these models could be less representative of primary tumors than previously thought, particularly when using late passages. ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3983
更新日期:2017-10-27 00:00:00
abstract::Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) has recently been defined based on a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. LBSL is an autosomal recessive disease, most often manifesting in early childho...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng2013
更新日期:2007-04-01 00:00:00
abstract::Little is known about the genetic regulation of medulloblastoma dissemination, but metastatic medulloblastoma is highly associated with poor outcome. We obtained expression profiles of 23 primary medulloblastomas clinically designated as either metastatic (M+) or non-metastatic (M0) and identified 85 genes whose expre...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng731
更新日期:2001-10-01 00:00:00
abstract::The central goal of human genetics is to understand the inherited basis of human variation in phenotypes, elucidating human physiology, evolution and disease. Rare mutations have been found underlying two thousand mendelian diseases; more recently, it has become possible to assess systematically the contribution of co...
journal_title:Nature genetics
pub_type: 杂志文章,评审
doi:10.1038/ng2080
更新日期:2007-07-01 00:00:00
abstract::Sialidase (neuraminidase, EC 3.2.1.18) catalyses the hydrolysis of terminal sialic acid residues of glyconjugates. Sialidase has been well studied in viruses and bacteria where it destroys the sialic acid-containing receptors at the surface of host cells, and mobilizes bacterial nutrients. In mammals, three types of s...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng0397-316
更新日期:1997-03-01 00:00:00
abstract::A new study identifies homozygous missense mutations in SGOL1, which encodes a component of the cohesin complex, in a newly described disorder termed Chronic Atrial and Intestinal Dysrhythmia (CAID) syndrome. These findings implicate cohesin in the regulation of intrinsic cardiac and intestinal rhythm and further expa...
journal_title:Nature genetics
pub_type: 评论,杂志文章
doi:10.1038/ng.3123
更新日期:2014-11-01 00:00:00