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HBO1 is required for the maintenance of leukaemia stem cells 期刊论文
NATURE, 2020, 577 (7789) : 266-+
作者:  MacPherson, Laura;  Anokye, Juliana;  Yeung, Miriam M.;  Lam, Enid Y. N.;  Chan, Yih-Chih;  Weng, Chen-Fang;  Yeh, Paul;  Knezevic, Kathy;  Butler, Miriam S.;  Hoegl, Annabelle;  Chan, Kah-Lok;  Burr, Marian L.;  Gearing, Linden J.;  Willson, Tracy;  Liu, Joy;  Choi, Jarny;  Yang, Yuqing;  Bilardi, Rebecca A.;  Falk, Hendrik;  Nghi Nguyen;  Stupple, Paul A.;  Peat, Thomas S.;  Zhang, Ming;  de Silva, Melanie;  Carrasco-Pozo, Catalina;  Avery, Vicky M.;  Khoo, Poh Sim;  Dolezal, Olan;  Dennis, Matthew L.;  Nuttall, Stewart;  Surjadi, Regina;  Newman, Janet;  Ren, Bin;  Leaver, David J.;  Sun, Yuxin;  Baell, Jonathan B.;  Dovey, Oliver;  Vassiliou, George S.;  Grebien, Florian;  Dawson, Sarah-Jane;  Street, Ian P.;  Monahan, Brendon J.;  Burns, Christopher J.;  Choudhary, Chunaram;  Blewitt, Marnie E.;  Voss, Anne K.;  Thomas, Tim;  Dawson, Mark A.
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)(1). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.


  
Simulation of Hubbard model physics in WSe2/WS2 moire superlattices 期刊论文
NATURE, 2020, 579 (7799) : 353-+
作者:  Stein, Reed M.;  Kang, Hye Jin;  McCorvy, John D.;  Glatfelter, Grant C.;  Jones, Anthony J.;  Che, Tao;  Slocum, Samuel;  Huang, Xi-Ping;  Savych, Olena;  Moroz, Yurii S.;  Stauch, Benjamin;  Johansson, Linda C.;  Cherezov, Vadim;  Kenakin, Terry;  Irwin, John J.;  Shoichet, Brian K.;  Roth, Bryan L.;  Dubocovich, Margarita L.
收藏  |  浏览/下载:8/0  |  提交时间:2020/07/03

Study of WSe2/WS2 moire superlattices reveals the phase diagram of the triangular-lattice Hubbard model, including a Mott insulating state at half-filling and a possible magnetic quantum phase transition near 0.6 filling.


The Hubbard model, formulated by physicist John Hubbard in the 1960s(1), is a simple theoretical model of interacting quantum particles in a lattice. The model is thought to capture the essential physics of high-temperature superconductors, magnetic insulators and other complex quantum many-body ground states(2,3). Although the Hubbard model provides a greatly simplified representation of most real materials, it is nevertheless difficult to solve accurately except in the one-dimensional case(2,3). Therefore, the physical realization of the Hubbard model in two or three dimensions, which can act as an analogue quantum simulator (that is, it can mimic the model and simulate its phase diagram and dynamics(4,5)), has a vital role in solving the strong-correlation puzzle, namely, revealing the physics of a large number of strongly interacting quantum particles. Here we obtain the phase diagram of the two-dimensional triangular-lattice Hubbard model by studying angle-aligned WSe2/WS2 bilayers, which form moire superlattices(6) because of the difference between the lattice constants of the two materials. We probe the charge and magnetic properties of the system by measuring the dependence of its optical response on an out-of-plane magnetic field and on the gate-tuned carrier density. At half-filling of the first hole moire superlattice band, we observe a Mott insulating state with antiferromagnetic Curie-Weiss behaviour, as expected for a Hubbard model in the strong-interaction regime(2,3,7-9). Above half-filling, our experiment suggests a possible quantum phase transition from an antiferromagnetic to a weak ferromagnetic state at filling factors near 0.6. Our results establish a new solid-state platform based on moire superlattices that can be used to simulate problems in strong-correlation physics that are described by triangular-lattice Hubbard models.


  
Late-stage oxidative C(sp(3))-H methylation 期刊论文
NATURE, 2020, 580 (7805) : 621-+
作者:  Fessler, Evelyn;  Eckl, Eva-Maria;  Schmitt, Sabine;  Mancilla, Igor Alves;  Meyer-Bender, Matthias F.;  Hanf, Monika;  Philippou-Massier, Julia;  Krebs, Stefan;  Zischka, Hans;  Jae, Lucas T.
收藏  |  浏览/下载:46/0  |  提交时间:2020/07/03

Frequently referred to as the '  magic methyl effect'  , the installation of methyl groups-especially adjacent (alpha) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules(1-3). However, existing methylation methods show limited scope and have not been demonstrated in complex settings(1). Here we report a regioselective and chemoselective oxidative C(sp(3))-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp(3))-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.


A manganese-catalysed oxidative C(sp(3))-H methylation method allows a methyl group to be selectively installed into medicinally important heterocycles, providing a way to improve pharmaceuticals and better understand the '  magic methyl effect'  .


  
Collisional cooling of ultracold molecules 期刊论文
NATURE, 2020, 580 (7802) : 197-+
作者:  Wang, Qinyang;  Wang, Yupeng;  Ding, Jingjin;  Wang, Chunhong;  Zhou, Xuehan;  Gao, Wenqing;  Huang, Huanwei;  Shao, Feng;  Liu, Zhibo
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

Since the original work on Bose-Einstein condensation(1,2), the use of quantum degenerate gases of atoms has enabled the quantum emulation of important systems in condensed matter and nuclear physics, as well as the study of many-body states that have no analogue in other fields of physics(3). Ultracold molecules in the micro- and nanokelvin regimes are expected to bring powerful capabilities to quantum emulation(4) and quantum computing(5), owing to their rich internal degrees of freedom compared to atoms, and to facilitate precision measurement and the study of quantum chemistry(6). Quantum gases of ultracold atoms can be created using collision-based cooling schemes such as evaporative cooling, but thermalization and collisional cooling have not yet been realized for ultracold molecules. Other techniques, such as the use of supersonic jets and cryogenic buffer gases, have reached temperatures limited to above 10 millikelvin(7,8). Here we show cooling of NaLi molecules to micro- and nanokelvin temperatures through collisions with ultracold Na atoms, with both molecules and atoms prepared in their stretched hyperfine spin states. We find a lower bound on the ratio of elastic to inelastic molecule-atom collisions that is greater than 50-large enough to support sustained collisional cooling. By employing two stages of evaporation, we increase the phase-space density of the molecules by a factor of 20, achieving temperatures as low as 220 nanokelvin. The favourable collisional properties of the Na-NaLi system could enable the creation of deeply quantum degenerate dipolar molecules and raises the possibility of using stretched spin states in the cooling of other molecules.


NaLi molecules are cooled to micro- and nanokelvin temperatures through collisions with ultracold Na atoms by using molecules and atoms in stretched hyperfine spin states and applying two evaporation stages.


  
Preindustrial (CH4)-C-14 indicates greater anthropogenic fossil CH4 emissions 期刊论文
NATURE, 2020, 578 (7795) : 409-+
作者:  Keener, Megan;  Hunt, Camden;  Carroll, Timothy G.;  Kampel, Vladimir;  Dobrovetsky, Roman;  Hayton, Trevor W.;  Menard, Gabriel
收藏  |  浏览/下载:25/0  |  提交时间:2020/05/13

Atmospheric methane (CH4) is a potent greenhouse gas, and its mole fraction has more than doubled since the preindustrial era(1). Fossil fuel extraction and use are among the largest anthropogenic sources of CH4 emissions, but the precise magnitude of these contributions is a subject of debate(2,3). Carbon-14 in CH4 ((CH4)-C-14) can be used to distinguish between fossil (C-14-free) CH4 emissions and contemporaneous biogenic sources  however, poorly constrained direct (CH4)-C-14 emissions from nuclear reactors have complicated this approach since the middle of the 20th century(4,5). Moreover, the partitioning of total fossil CH4 emissions (presently 172 to 195 teragrams CH4 per year)(2,3) between anthropogenic and natural geological sources (such as seeps and mud volcanoes) is under debate  emission inventories suggest that the latter account for about 40 to 60 teragrams CH4 per year(6,7). Geological emissions were less than 15.4 teragrams CH4 per year at the end of the Pleistocene, about 11,600 years ago(8), but that period is an imperfect analogue for present-day emissions owing to the large terrestrial ice sheet cover, lower sea level and extensive permafrost. Here we use preindustrial-era ice core (CH4)-C-14 measurements to show that natural geological CH4 emissions to the atmosphere were about 1.6 teragrams CH4 per year, with a maximum of 5.4 teragrams CH4 per year (95 per cent confidence limit)-an order of magnitude lower than the currently used estimates. This result indicates that anthropogenic fossil CH4 emissions are underestimated by about 38 to 58 teragrams CH4 per year, or about 25 to 40 per cent of recent estimates. Our record highlights the human impact on the atmosphere and climate, provides a firm target for inventories of the global CH4 budget, and will help to inform strategies for targeted emission reductions(9,10).


Isotopic evidence from ice cores indicates that preindustrial-era geological methane emissions were lower than previously thought, suggesting that present-day emissions of methane from fossil fuels are underestimated.


  
Spontaneous gyrotropic electronic order in a transition-metal dichalcogenide 期刊论文
NATURE, 2020, 578 (7796) : 545-+
作者:  Kum, Hyun S.;  Lee, Hyungwoo;  Kim, Sungkyu;  Lindemann, Shane;  Kong, Wei;  Qiao, Kuan;  Chen, Peng;  Irwin, Julian;  Lee, June Hyuk;  Xie, Saien;  Subramanian, Shruti;  Shim, Jaewoo;  Bae, Sang-Hoon;  Choi, Chanyeol;  Ranno, Luigi;  Seo, Seungju;  Lee, Sangho;  Bauer, Jackson;  Li, Huashan;  Lee, Kyusang;  Robinson, Joshua A.;  Ross, Caroline A.;  Schlom, Darrell G.;  Rzchowski, Mark S.;  Eom, Chang-Beom;  Kim, Jeehwan
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/03

Chirality is ubiquitous in nature, and populations of opposite chiralities are surprisingly asymmetric at fundamental levels(1,2). Examples range from parity violation in the subatomic weak force to homochirality in biomolecules. The ability to achieve chirality-selective synthesis (chiral induction) is of great importance in stereochemistry, molecular biology and pharmacology(2). In condensed matter physics, a crystalline electronic system is geometrically chiral when it lacks mirror planes, space-inversion centres or rotoinversion axes(1). Typically, geometrical chirality is predefined by the chiral lattice structure of a material, which is fixed on formation of the crystal. By contrast, in materials with gyrotropic order(3-6), electrons spontaneously organize themselves to exhibit macroscopic chirality in an originally achiral lattice. Although such order-which has been proposed as the quantum analogue of cholesteric liquid crystals-has attracted considerable interest(3-15), no clear observation or manipulation of gyrotropic order has been achieved so far. Here we report the realization of optical chiral induction and the observation of a gyrotropically ordered phase in the transition-metal dichalcogenide semimetal 1T-TiSe2. We show that shining mid-infrared circularly polarized light on 1T-TiSe2 while cooling it below the critical temperature leads to the preferential formation of one chiral domain. The chirality of this state is confirmed by the measurement of an out-of-plane circular photogalvanic current, the direction of which depends on the optical induction. Although the role of domain walls requires further investigation with local probes, the methodology demonstrated here can be applied to realize and control chiral electronic phases in other quantum materials(4,16).


Optical chiral induction and spontaneous gyrotropic electronic order are realized in the transition-metal chalcogenide 1T-TiSe2 by using illumination with mid-infrared circularly polarized light and simultaneous cooling below the critical temperature.


  
Structure and mechanism of the ER-based glucosyltransferase ALG6 期刊论文
NATURE, 2020, 579 (7799) : 443-+
作者:  van Veen, Sarah;  Martin, Shaun;  Van den Haute, Chris;  Benoy, Veronick;  Lyons, Joseph;  Vanhoutte, Roeland;  Kahler, Jan Pascal;  Decuypere, Jean-Paul;  Gelders, Geraldine;  Lambie, Eric;  Zielich, Jeffrey;  Swinnen, Johannes V.;  Annaert, Wim;  Agostinis, Patrizia;  Ghesquiere, Bart;  Verhelst, Steven;  Baekelandt, Veerle;  Eggermont, Jan;  Vangheluwe, Peter
收藏  |  浏览/下载:13/0  |  提交时间:2020/07/03

Analyses reveal a previously undescribed transmembrane protein fold in the endoplasmic reticulum-based glucosyltransferase ALG6 and provide a structural basis for understanding the glucose transfer mechanism.


In eukaryotic protein N-glycosylation, a series of glycosyltransferases catalyse the biosynthesis of a dolichylpyrophosphate-linked oligosaccharide before its transfer onto acceptor proteins(1). The final seven steps occur in the lumen of the endoplasmic reticulum (ER) and require dolichylphosphate-activated mannose and glucose as donor substrates(2). The responsible enzymes-ALG3, ALG9, ALG12, ALG6, ALG8 and ALG10-are glycosyltransferases of the C-superfamily (GT-Cs), which are loosely defined as containing membrane-spanning helices and processing an isoprenoid-linked carbohydrate donor substrate(3,4). Here we present the cryo-electron microscopy structure of yeast ALG6 at 3.0 angstrom resolution, which reveals a previously undescribed transmembrane protein fold. Comparison with reported GT-C structures suggests that GT-C enzymes contain a modular architecture with a conserved module and a variable module, each with distinct functional roles. We used synthetic analogues of dolichylphosphate-linked and dolichylpyrophosphate-linked sugars and enzymatic glycan extension to generate donor and acceptor substrates using purified enzymes of the ALG pathway to recapitulate the activity of ALG6 in vitro. A second cryo-electron microscopy structure of ALG6 bound to an analogue of dolichylphosphate-glucose at 3.9 angstrom resolution revealed the active site of the enzyme. Functional analysis of ALG6 variants identified a catalytic aspartate residue that probably acts as a general base. This residue is conserved in the GT-C superfamily. Our results define the architecture of ER-luminal GT-C enzymes and provide a structural basis for understanding their catalytic mechanisms.


  
Structure of SAGA and mechanism of TBP deposition on gene promoters 期刊论文
NATURE, 2020, 577 (7792) : 711-+
作者:  Xue, Jenny Y.;  Zhao, Yulei;  Aronowitz, Jordan;  Mai, Trang T.;  Vides, Alberto;  Qeriqi, Besnik;  Kim, Dongsung;  Li, Chuanchuan;  de Stanchina, Elisa;  Mazutis, Linas;  Risso, Davide;  Lito, Piro
收藏  |  浏览/下载:33/0  |  提交时间:2020/07/03

SAGA (Spt-Ada-Gcn5-acetyltransferase) is a 19-subunit complex that stimulates transcription via two chromatin-modifying enzymatic modules and by delivering the TATA box binding protein (TBP) to nucleate the pre-initiation complex on DNA, a pivotal event in the expression of protein-encoding genes(1). Here we present the structure of yeast SAGA with bound TBP. The core of the complex is resolved at 3.5 angstrom resolution (0.143 Fourier shell correlation). The structure reveals the intricate network of interactions that coordinate the different functional domains of SAGA and resolves an octamer of histone-fold domains at the core of SAGA. This deformed octamer deviates considerably from the symmetrical analogue in the nucleosome and is precisely tuned to establish a peripheral site for TBP, where steric hindrance represses binding of spurious DNA. Complementary biochemical analysis points to a mechanism for TBP delivery and release from SAGA that requires transcription factor IIA and whose efficiency correlates with the affinity of DNA to TBP. We provide the foundations for understanding the specific delivery of TBP to gene promoters and the multiple roles of SAGA in regulating gene expression.


Structural studies on the yeast transcription coactivator complex SAGA (Spt-Ada-Gcn5-acetyltransferase) provide insights into the mechanism of initiation of regulated transcription by this multiprotein complex, which is conserved among eukaryotes.