Abstract:
:Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression.
journal_name
Naturejournal_title
Natureauthors
Adams EJ,Karthaus WR,Hoover E,Liu D,Gruet A,Zhang Z,Cho H,DiLoreto R,Chhangawala S,Liu Y,Watson PA,Davicioni E,Sboner A,Barbieri CE,Bose R,Leslie CS,Sawyers CLdoi
10.1038/s41586-019-1318-9subject
Has Abstractpub_date
2019-07-01 00:00:00pages
408-412issue
7765eissn
0028-0836issn
1476-4687pii
10.1038/s41586-019-1318-9journal_volume
571pub_type
杂志文章相关文献
NATURE文献大全abstract::The visual recognition of three-dimensional (3-D) objects on the basis of their shape poses at least two difficult problems. First, there is the problem of variable illumination, which can be addressed by working with relatively stable features such as intensity edges rather than the raw intensity images. Second, ther...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/343263a0
更新日期:1990-01-18 00:00:00
abstract:: ...
journal_title:Nature
pub_type: 新闻
doi:10.1038/d41586-019-00292-w
更新日期:2019-02-01 00:00:00
abstract::The discovery of intervening sequences (introns) in DNA led Gilbert and Tonegawa to suggest that a new protein could have been produced by bringing together certain segments of pre-existing ones. However, Blake argued that if DNA was so organized that coding sequences (exons) correspond to structural as well as functi...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/291090a0
更新日期:1981-05-07 00:00:00
abstract::Protein structures are stabilized by hydrophobic and van der Waals forces, and by hydrogen bonds. The relation between these thermodynamic quantities and the actual three-dimensional structure of proteins can not be calculated precisely. However, certain empirical relations have been discovered. Hydrophobic energy is ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/328834a0
更新日期:1987-08-27 00:00:00
abstract::The Nuffield Council on Bioethics suggests that introgression of genetic material into related species in centres of crop biodiversity is an insufficient justification to bar the use of genetically modified crops in the developing world. They consider that a precautionary approach to forgo the possible benefits invoke...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature03048
更新日期:2004-11-11 00:00:00
abstract::Recently, a class of protein antigens of high relative molecular mass (Mt) which can induce protective immunity against blood-stage malaria has been identified. In Plasmodium falciparum the protein has a Mr of approximately 195,000 (P195). It is the precursor of three proteins of Mr 83,000 (83K), 42K and 19K which are...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/317270a0
更新日期:1985-09-19 00:00:00
abstract::Hydrothermal vents are ephemeral because of frequent volcanic and tectonic activities associated with crust formation. Although the larvae of hydrothermal vent fauna can rapidly colonize new vent sites separated by tens to hundreds of kilometres, the mechanisms by which these larvae disperse and recruit are not unders...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35075063
更新日期:2001-05-03 00:00:00
abstract::The assembly of ribosomes in bacterial cells is a complex process that remains poorly characterized. The in vitro assembly of active ribosomal subunits from purified RNA and protein components indicates that all of the information for proper assembly resides in the primary sequences of these macromolecules. On the oth...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/336496a0
更新日期:1988-12-01 00:00:00
abstract::The recent decades-long decline in East African rainfall suggests that multidecadal variability is an important component of the climate of this vulnerable region. Prior work based on analysing the instrumental record implicates both Indian and Pacific ocean sea surface temperatures (SSTs) as possible drivers of East ...
journal_title:Nature
pub_type: 历史文章,杂志文章
doi:10.1038/nature11785
更新日期:2013-01-17 00:00:00
abstract::The elevation history of the Tibetan plateau provides direct insight into the tectonic processes associated with continent-continent collisions. Here we present oxygen-isotope-based estimates of the palaeo-altimetry of late Eocene and younger deposits of the Lunpola basin in the centre of the plateau, which indicate t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04506
更新日期:2006-02-09 00:00:00
abstract::With the current shortage in fetal bovine serum, researchers are turning to a variety of options for cell and tissue culture. ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/334547a0
更新日期:1988-08-11 00:00:00
abstract::The spontaneously hypertensive rat and the stroke-prone spontaneously hypertensive rat are useful models for human hypertension. In these strains hypertension is a polygenic trait, in which both autosomal and sex-linked genes can influence blood pressure. Linkage studies in crosses between the stroke-prone spontaneous...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/353521a0
更新日期:1991-10-10 00:00:00
abstract::Obesity is a disorder of energy balance, indicating a chronic disequilibrium between energy intake and expenditure. Recently, the mouse ob gene, and subsequently its human and rat homologues, have been cloned. The ob gene product, leptin, is expressed exclusively in adipose tissue, and appears to be a signalling facto...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/377527a0
更新日期:1995-10-12 00:00:00
abstract::Rab GTPases regulate all stages of membrane trafficking, including vesicle budding, cargo sorting, transport, tethering and fusion. In the inactive (GDP-bound) conformation, accessory factors facilitate the targeting of Rab GTPases to intracellular compartments. After nucleotide exchange to the active (GTP-bound) conf...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature03798
更新日期:2005-07-21 00:00:00
abstract::Genetic manipulations of insect populations for pest control have been advocated for some time, but there are few cases where manipulated individuals have been released in the field and no cases where they have successfully invaded target populations. Population transformation using the intracellular bacterium Wolbach...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10356
更新日期:2011-08-24 00:00:00
abstract::The neocortex of the adult brain consists of neurons and glia that are generated by precursor cells of the embryonic ventricular zone. In general, glia are generated after neurons during development, but radial glia are an exception to this rule. Radial glia are generated before neurogenesis and guide neuronal migrati...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35055553
更新日期:2001-02-08 00:00:00
abstract::Genetic models predict that genomic rearrangement in hybrids can facilitate reproductive isolation and the formation of new species by preventing gene flow between the parent species and hybrid (sunflowers are an example). The mechanism underlying hybridization-induced chromosome remodelling is as yet unknown, althoug...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/29985
更新日期:1998-05-07 00:00:00
abstract::Many fermentative bacteria obtain energy for growth by reactions in which the change in free energy (DeltaG') is less than that needed to synthesize ATP. These bacteria couple substrate metabolism directly to ATP synthesis, however, by classical phosphoryl transfer reactions. An explanation for the energy economy of t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/415454a
更新日期:2002-01-24 00:00:00
abstract::The Ran proteins constitute a distinct branch of the superfamily of Ras-related GTP-binding proteins which function as molecular switches cycling between GTP-bound 'on' and GDP-bound 'off' states. Ran is located predominantly in the nucleus of eukaryotic cells and is involved in the nuclear import of proteins as well ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/374378a0
更新日期:1995-03-23 00:00:00
abstract::Cellulose is the major polysaccharide component of plant cell walls and is the most abundant organic compound on the planet. A number of bacterial and fungal organisms can use cellulose as a food source, possessing cellulases (cellobiohydrolases and endoglucanases) that can catalyse the hydrolysis of the beta-(1,4) gl...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/365362a0
更新日期:1993-09-23 00:00:00
abstract::Glucagon is a 29-amino-acid peptide released from the α-cells of the islet of Langerhans, which has a key role in glucose homeostasis. Glucagon action is transduced by the class B G-protein-coupled glucagon receptor (GCGR), which is located on liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart and p...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature17414
更新日期:2016-05-12 00:00:00
abstract::Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota. In the gut, the fraction of strict anaerobes increases from proximal to distal, reaching 99% of bacterial species in the colon. At colonic mucosa, oxygen partial pressure is below 25% of airborne oxygen con...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09674
更新日期:2011-01-20 00:00:00
abstract::The dispute among federal agencies over regulation of commercial biotechnology has been addressed in the Federal Register by the Office of Science and Technology Policy (OSTP), which says the Recombinant DNA Advisory Committee of the National Institutes of Health should continue to oversee biomedical research in this ...
journal_title:Nature
pub_type: 新闻
doi:10.1038/313085b0
更新日期:1985-01-10 00:00:00
abstract::Myosin, a major contractile protein, characteristically possesses a long coiled-coil alpha-helical tail and two heads. Each head contains both an actin binding site and an ATPase site and is formed from the NH2-terminal half of one of the two heavy chains (relative molecular mass, Mr, 200,000) and a pair of light chai...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/324078a0
更新日期:1986-11-06 00:00:00
abstract::Four incorrect figure citations in this Letter have been corrected online. ...
journal_title:Nature
pub_type: 杂志文章,已发布勘误
doi:10.1038/s41586-018-0560-x
更新日期:2018-11-01 00:00:00
abstract::Thermoelectric materials are of interest for applications as heat pumps and power generators. The performance of thermoelectric devices is quantified by a figure of merit, ZT, where Z is a measure of a material's thermoelectric properties and T is the absolute temperature. A material with a figure of merit of around u...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35098012
更新日期:2001-10-11 00:00:00
abstract::The guinea-pig (Cavia porcellus), traditionally classified as a New World hystricomorph rodent, often shows anomalous morphological and molecular features in comparison with other eutherian mammals. For example, its insulin differs from that of other mammals in anabolic and growth-promoting activities and in its capab...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/351649a0
更新日期:1991-06-20 00:00:00
abstract::The factor for inversion stimulation, FIS, is involved in several cellular processes, including site-specific recombination and transcriptional activation. In the reactions catalysed by the DNA invertases Gin, Hin and Cin, FIS stimulates recombination by binding to an enhancer sequence. Within the enhancer, two FIS di...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/349178a0
更新日期:1991-01-10 00:00:00
abstract::Mammalian neurons contain at least three types of excitatory amino-acid receptors, selectively activated by N-methyl-D-aspartate (NMDA) or aspartate, (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate ((S)-AMPA) and kainate. An important aspect of NMDA receptors is their regulation by a variety of factors such...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/345347a0
更新日期:1990-05-24 00:00:00
abstract::The vasopressor angiotensin II regulates vascular contractility and blood pressure through binding to type 1 angiotensin II receptors (AT1; refs 1, 2). Bradykinin, a vasodepressor, is a functional antagonist of angiotensin II (ref. 3). The two hormone systems are interconnected by the angiotensin-converting enzyme, wh...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35024095
更新日期:2000-09-07 00:00:00