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Impaired cell fate through gain-of-function mutations in a chromatin reader 期刊论文
NATURE, 2020, 577 (7788) : 121-+
作者:  Wan, Liling;  Chong, Shasha;  Xuan, Fan;  Liang, Angela;  Cui, Xiaodong;  Gates, Leah;  Carroll, Thomas S.;  Li, Yuanyuan;  Feng, Lijuan;  Chen, Guochao;  Wang, Shu-Ping;  Ortiz, Michael V.;  Daley, Sara K.;  Wang, Xiaolu;  Xuan, Hongwen;  Kentsis, Alex;  Muir, Tom W.;  Roeder, Robert G.;  Li, Haitao;  Li, Wei;  Tjian, Robert;  Wen, Hong;  Allis, C. David
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/03

Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by '  reader'  proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatinreader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.


  
The water lily genome and the early evolution of flowering plants 期刊论文
NATURE, 2020, 577 (7788) : 79-+
作者:  Zhang, Liangsheng;  Chen, Fei;  Zhang, Xingtan;  Li, Zhen;  Zhao, Yiyong;  Lohaus, Rolf;  Chang, Xiaojun;  Dong, Wei;  Ho, Simon Y. W.;  Liu, Xing;  Song, Aixia;  Chen, Junhao;  Guo, Wenlei;  Wang, Zhengjia;  Zhuang, Yingyu;  Wang, Haifeng;  Chen, Xuequn;  Hu, Juan;  Liu, Yanhui;  Qin, Yuan;  Wang, Kai;  Dong, Shanshan;  Liu, Yang;  Zhang, Shouzhou;  Yu, Xianxian;  Wu, Qian;  Wang, Liangsheng;  Yan, Xueqing;  Jiao, Yuannian;  Kong, Hongzhi;  Zhou, Xiaofan;  Yu, Cuiwei;  Chen, Yuchu;  Li, Fan;  Wang, Jihua;  Chen, Wei;  Chen, Xinlu;  Jia, Qidong;  Zhang, Chi;  Jiang, Yifan;  Zhang, Wanbo;  Liu, Guanhua;  Fu, Jianyu;  Chen, Feng;  Ma, Hong;  Van de Peer, Yves;  Tang, Haibao
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

Water lilies belong to the angiosperm order Nymphaeales. Amborellales, Nymphaeales and Austrobaileyales together form the so-called ANA-grade of angiosperms, which are extant representatives of lineages that diverged the earliest from the lineage leading to the extant mesangiosperms(1-3). Here we report the 409-megabase genome sequence of the blue-petal water lily (Nymphaea colorata). Our phylogenomic analyses support Amborellales and Nymphaeales as successive sister lineages to all other extant angiosperms. The N. colorata genome and 19 other water lily transcriptomes reveal a Nymphaealean whole-genome duplication event, which is shared by Nymphaeaceae and possibly Cabombaceae. Among the genes retained from this whole-genome duplication are homologues of genes that regulate flowering transition and flower development. The broad expression of homologues of floral ABCE genes in N. colorata might support a similarly broadly active ancestral ABCE model of floral organ determination in early angiosperms. Water lilies have evolved attractive floral scents and colours, which are features shared with mesangiosperms, and we identified their putative biosynthetic genes in N. colorata. The chemical compounds and biosynthetic genes behind floral scents suggest that they have evolved in parallel to those in mesangiosperms. Because of its unique phylogenetic position, the N. colorata genome sheds light on the early evolution of angiosperms.


  
Layered nanocomposites by shear-flow-induced alignment of nanosheets (vol 580, pg 210, 2020) 期刊论文
NATURE, 2020, 582 (7811) : E4-E4
作者:  Chen, Guorui;  Sharpe, Aaron L.;  Fox, Eli J.;  Zhang, Ya-Hui;  Wang, Shaoxin;  Jiang, Lili;  Lyu, Bosai;  Li, Hongyuan;  Watanabe, Kenji;  Taniguchi, Takashi;  Shi, Zhiwen;  Senthil, T.;  Goldhaber-Gordon, David;  Zhang, Yuanbo;  Wang, Feng
收藏  |  浏览/下载:30/0  |  提交时间:2020/07/03
Hidden neural states underlie canary song syntax 期刊论文
NATURE, 2020
作者:  Bao, Han;  Duan, Junlei;  Jin, Shenchao;  Lu, Xingda;  Li, Pengxiong;  Qu, Weizhi;  Wang, Mingfeng;  Novikova, Irina;  Mikhailov, Eugeniy E.;  Zhao, Kai-Feng;  Molmer, Klaus;  Shen, Heng;  Xiao, Yanhong
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/03

Neurons in the canary premotor cortex homologue encode past song phrases and transitions, carrying information relevant to future choice of phrases as '  hidden states'  during song.


Coordinated skills such as speech or dance involve sequences of actions that follow syntactic rules in which transitions between elements depend on the identities and order of past actions. Canary songs consist of repeated syllables called phrases, and the ordering of these phrases follows long-range rules(1)in which the choice of what to sing depends on the song structure many seconds prior. The neural substrates that support these long-range correlations are unknown. Here, using miniature head-mounted microscopes and cell-type-specific genetic tools, we observed neural activity in the premotor nucleus HVC(2-4)as canaries explored various phrase sequences in their repertoire. We identified neurons that encode past transitions, extending over four phrases and spanning up to four seconds and forty syllables. These neurons preferentially encode past actions rather than future actions, can reflect more than one song history, and are active mostly during the rare phrases that involve history-dependent transitions in song. These findings demonstrate that the dynamics of HVC include '  hidden states'  that are not reflected in ongoing behaviour but rather carry information about prior actions. These states provide a possible substrate for the control of syntax transitions governed by long-range rules.


  
The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K 期刊论文
NATURE, 2020
作者:  Chen, Guorui;  Sharpe, Aaron L.;  Fox, Eli J.;  Zhang, Ya-Hui;  Wang, Shaoxin;  Jiang, Lili;  Lyu, Bosai;  Li, Hongyuan;  Watanabe, Kenji;  Taniguchi, Takashi;  Shi, Zhiwen;  Senthil, T.;  Goldhaber-Gordon, David;  Zhang, Yuanbo;  Wang, Feng
收藏  |  浏览/下载:44/0  |  提交时间:2020/07/03

The cyclin-dependent kinase inhibitor CR8 acts as a molecular glue compound by inducing the formation of a complex between CDK12-cyclin K and DDB1, which results in the ubiquitination and degradation of cyclin K.


Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation(1). Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets(2). They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines(3-5), we identify CR8-a cyclin-dependent kinase (CDK) inhibitor(6)-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.


  
Nanoplasma-enabled picosecond switches for ultrafast electronics (vol 579, pg 534, 2020) 期刊论文
NATURE, 2020, 580 (7803) : E8-E8
作者:  Li, Jing;  Xu, Chuanliang;  Lee, Hyung Joo;  Ren, Shancheng;  Zi, Xiaoyuan;  Zhang, Zhiming;  Wang, Haifeng;  Yu, Yongwei;  Yang, Chenghua;  Gao, Xiaofeng;  Hou, Jianguo;  Wang, Linhui;  Yang, Bo;  Yang, Qing;  Ye, Huamao;  Zhou, Tie;  Lu, Xin;  Wang, Yan;  Qu, Min;  Yang, Qingsong;  Zhang, Wenhui;  Shah, Nakul M.;  Pehrsson, Erica C.;  Wang, Shuo;  Wang, Zengjun;  Jiang, Jun;  Zhu, Yan;  Chen, Rui;  Chen, Huan;  Zhu, Feng;  Lian, Bijun;  Li, Xiaoyun;  Zhang, Yun;  Wang, Chao;  Wang, Yue;  Xiao, Guangan;  Jiang, Junfeng;  Yang, Yue;  Liang, Chaozhao;  Hou, Jianquan;  Han, Conghui;  Chen, Ming;  Jiang, Ning;  Zhang, Dahong;  Wu, Song;  Yang, Jinjian;  Wang, Tao;  Chen, Yongliang;  Cai, Jiantong;  Yang, Wenzeng;  Xu, Jun;  Wang, Shaogang;  Gao, Xu;  Wang, Ting;  Sun, Yinghao
收藏  |  浏览/下载:18/0  |  提交时间:2020/07/03
Integrating genomic features for non-invasive early lung cancer detection 期刊论文
NATURE, 2020, 580 (7802) : 245-+
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:15/0  |  提交时间:2020/07/03

Circulating tumour DNA in blood is analysed to identify genomic features that distinguish early-stage lung cancer patients from risk-matched controls, and these are integrated into a machine-learning method for blood-based lung cancer screening.


Radiologic screening of high-risk adults reduces lung-cancer-related mortality(1,2)  however, a small minority of eligible individuals undergo such screening in the United States(3,4). The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)(5), a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed '  lung cancer likelihood in plasma'  (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.


  
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.


  
Signatures of self-organized criticality in an ultracold atomic gas (vol 577, pg 481, 2020) 期刊论文
NATURE, 2020, 579 (7800) : E13-E13
作者:  Zhou, Xiaoling;  Feng, Zongqiang;  Zhu, Linli;  Xu, Jianing;  Miyagi, Lowell;  Dong, Hongliang;  Sheng, Hongwei;  Wang, Yanju;  Li, Quan;  Ma, Yanming;  Zhang, Hengzhong;  Yan, Jinyuan;  Tamura, Nobumichi;  Kunz, Martin;  Lutker, Katie;  Huang, Tianlin;  Hughes, Darcy A.;  Huang, Xiaoxu;  Chen, Bin
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

An amendment to this paper has been published and can be accessed via a link at the top of the paper.


  
A self-activating orphan receptor 期刊论文
NATURE, 2020, 579 (7797) : 35-35
作者:  Wang, Lin;  Wu, Juehui;  Li, Jun;  Yang, Hua;  Tang, Tianqi;  Liang, Haijiao;  Zuo, Mianyong;  Wang, Jie;  Liu, Haipeng;  Liu, Feng;  Chen, Jianxia;  Liu, Zhonghua;  Wang, Yang;  Peng, Cheng;  Wu, Xiangyang;  Zheng, Ruijuan;  Huang, Xiaochen;  Ran, Yajun;  Rao, Zihe;  Ge, Baoxue
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

The first 3D structure of a full-length G-protein-coupled receptor whose natural activator is unknown has been determined, providing insights into an unusual mode of activation and a basis for discovering therapeutics.