Table of Contents
Sep 2019
Volume 29, Issue 9, Page 687-778
About the Cover:  
  RESEARCH HIGHLIGHTS   ORIGINAL ARTICLES   EDITORIAL
  REVIEW   LETTER TO EDITOR   CORRIGENDA
  RESEARCH HIGHLIGHTS
Sebastian Memczak 1,2, Yanjiao Shao 1,3 and Juan Carlos Izpisua Belmonte 1
https://doi.org/10.1038/s41422-019-0188-x
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Commonly used Cas9:gRNA programmed base-editor complexes introduce frequent, so far unrecognized RNA off-target edits. Novel, engineered enzymes may overcome this hurdle towards clinical applications of genome engineering.
Ganes C. Sen1 and Bryan R. G. Williams 1,2
https://doi.org/10.1038/s41422-019-0207-y
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Host-virus homeostasis is intricately regulated at multiple steps of both interferon (IFN) induction and IFN action; a recent paper by Zhou et al. has revealed a new feature of this complex regulation. They report the discovery of an IFN-inducible cytoplasmic long non-coding RNA, lncLrrc55-AS, which promotes IRF3 phosphorylation by inactivating the phosphatase PP2A, thus providing a positive feedback loop to IFN induction.
Laurence Zitvogel 1,2,3 and Guido Kroemer 4,5,6,7,8
https://doi.org/10.1038/s41422-019-0186-z
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Ferroptosis is an atypical cell death modality involving the oxidative destruction of cellular membranes following the failure of a glutathione-dependent antioxidant system. A recent paper by Wang et al. demonstrates that interferon-γ produced by tumor-infiltrating T cells can kill cancer cells through the induction of ferroptosis.
Susan M. Abmayr 1,2 and Jerry L. Workman 1
https://doi.org/10.1038/s41422-019-0211-2
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Recent studies have demonstrated the addition and removal of a smorgasbord of site-specific acylation modifications on lysine residues of histone tails. The study by Zhang et al. now shows how the SIRT3 histone deacylase exhibits class specificity, acting on only a subset of β-hydroxybutyrylated lysines.
  ORIGINAL ARTICLES
Bingqing Xie 1,2, Da Sun 1,2, Yuanyuan Du1, Jun Jia1, Shicheng Sun 1, Jun Xu1, Yifang Liu3, Chengang Xiang1, Sitong Chen1,Huangfan Xie 1, Qiming Wang1, Guangya Li1, Xuehui LYU4, Hui Shen4, Shiyu Li4, Min Wu5, Xiaonan Zhang5, Yue Pu6, Kuanhui Xiang7,Weifeng Lai1, Peng Du4, Zhenghong Yuan8, Cheng Li3, Yan Shi1, Shichun Lu9 and Hongkui Deng 1,2
https://doi.org/10.1038/s41422-019-0196-x
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Terminally differentiated cells can be generated by lineage reprogramming, which is, however, hindered by incomplete conversion with residual initial cell identity and partial functionality. Here, we demonstrate a new reprogramming strategy by mimicking the natural regeneration route, which permits generating expandable hepatic progenitor cells and functionally competent human hepatocytes. Fibroblasts were first induced into human hepatic progenitor-like cells (hHPLCs), which could robustly expand in vitro and efficiently engraft in vivo. Moreover, hHPLCs could be efficiently induced into mature human hepatocytes (hiHeps) in vitro, whose molecular identity highly resembles primary human hepatocytes (PHHs). Most importantly, hiHeps could be generated in large quantity and were functionally competent to replace PHHs for drug-metabolism estimation, toxicity prediction and hepatitis B virus infection modeling. Our results highlight the advantages of the progenitor stage for successful lineage reprogramming. This strategy is promising for generating other mature human cell types by lineage reprogramming.
Jinwu Chen1, Xiaojie Li1, Ling Li 1,2, Ting Zhang1, Qing Zhang1, Fangming Wu3, Diyue Wang1, Hongze Hu4, Changlin Tian 3,5 ,Dongsheng Liao1, Liang Zhao1, Danxia Song1, Yongyun Zhao1, Chuanfang Wu1 and Xu Song 1,2
https://doi.org/10.1038/s41422-019-0202-3
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Infections caused by drug-resistant “superbugs” pose an urgent public health threat due to the lack of effective drugs; however, certain mammalian proteins with intrinsic antibacterial activity might be underappreciated. Here, we reveal an antibacterial property against Gram-negative bacteria for factors VII, IX and X, three proteins with well-established roles in initiation of the coagulation cascade. These factors exert antibacterial function via their light chains (LCs). Unlike many antibacterial agents that target cell metabolism or the cytoplasmic membrane, the LCs act by hydrolyzing the major components of bacterial outer membrane, lipopolysaccharides, which are crucial for the survival of Gram-negative bacteria. The LC of factor VII exhibits in vitro efficacy towards all Gram-negative bacteria tested, including extensively drug-resistant (XDR) pathogens, at nanomolar concentrations. It is also highly effective in combating XDR Pseudomonas aeruginosa and Acinetobacter baumannii infections in vivo. Through decoding a unique mechanism whereby factors VII, IX and X behave as antimicrobial proteins, this study advances our understanding of the coagulation system in host defense, and suggests that these factors may participate in the pathogenesis of coagulation disorder-related diseases such as sepsis via their dual functions in blood coagulation and resistance to infection. Furthermore, this study may offer new strategies for combating Gram-negative “superbugs”.
Junya Peng1, Bao-Fa Sun 2,3,4, Chuan-Yuan Chen 2,3, Jia-Yi Zhou 2,3, Yu-Sheng Chen 2,3, Hao Chen 5, Lulu Liu1, Dan Huang1, Jialin Jiang5,Guan-Shen Cui 2,3, Ying Yang 2,3,4, Wenze Wang6, Dan Guo 1,7, Menghua Dai5, Junchao Guo5, Taiping Zhang5, Quan Liao5, Yi Liu8,Yong-Liang Zhao 2,3,4, Da-Li Han 2,3,4, Yupei Zhao 5,8, Yun-Gui Yang 2,3,4 and Wenming Wu5
https://doi.org/10.1038/s41422-019-0195-y
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Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. To comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, we employed single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases, and identified diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, in PDAC. We found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, we found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, our findings provide a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.
Jiachang Wang 1,2, Xi Liu1, An Zhang3, Yulong Ren2, Fuqing Wu2, Gang Wang3, Yang Xu1, Cailin Lei2, Shanshan Zhu2, Tian Pan1, Yongfei Wang1, Huan Zhang1, Fan Wang1, Yan-Qiu Tan3, Yupeng Wang2, Xin Jin2, Sheng Luo2, Chunlei Zhou1, Xiao Zhang1, Jinling Liu2,Shuai Wang2
, Lingzhi Meng2, Yihua Wang1, Xi Chen3, Qibing Lin2, Xin Zhang2, Xiuping Guo2, Zhijun Cheng2, Jiulin Wang2, Yunlu Tian1, Shijia Liu1, Ling Jiang1, Chuanyin Wu2, Ertao Wang 3, Jian-Min Zhou 4, Yong-Fei Wang 3, Haiyang Wang 2 and Jianmin Wan 2
https://doi.org/10.1038/s41422-019-0219-7
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The transient elevation of cytoplasmic calcium is essential for pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). However, the calcium channels responsible for this process have remained unknown. Here, we show that rice CDS1 (CELL DEATH and SUSCEPTIBLE to BLAST 1) encoding OsCNGC9, a cyclic nucleotide-gated channel protein, positively regulates the resistance to rice blast disease. We show that OsCNGC9 mediates PAMP-induced Ca2+ influx and that this event is critical for PAMPs-triggered ROS burst and induction of PTI-related defense gene expression. We further show that a PTI-related receptor-like cytoplasmic kinase OsRLCK185 physically interacts with and phosphorylates OsCNGC9 to activate its channel activity. Our results suggest a signaling cascade linking pattern recognition to calcium channel activation, which is required for initiation of PTI and disease resistance in rice.
Tingting Hou1, Rufeng Zhang1, Chongshu Jian1, Wanqiu Ding1, Yanru Wang1, Shukuan Ling2, Qi Ma1, Xinli Hu1, Heping Cheng1 and Xianhua Wang 1
https://doi.org/10.1038/s41422-019-0208-x
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The impairment of mitochondrial bioenergetics, often coupled with exaggerated reactive oxygen species (ROS) production, is a fundamental disease mechanism in organs with a high demand for energy, including the heart. Building a more robust and safer cellular powerhouse holds the promise for protecting these organs in stressful conditions. Here, we demonstrate that NADH:ubiquinone oxidoreductase subunit AB1 (NDUFAB1), also known as mitochondrial acyl carrier protein, acts as a powerful cardio-protector by conferring greater capacity and efficiency of mitochondrial energy metabolism. In particular, NDUFAB1 not only serves as a complex I subunit, but also coordinates the assembly of respiratory complexes I, II, and III, and supercomplexes, through regulating iron-sulfur biosynthesis and complex I subunit stability. Cardiac-specific deletion of Ndufab1 in mice caused defective bioenergetics and elevated ROS levels, leading to progressive dilated cardiomyopathy and eventual heart failure and sudden death. Overexpression of Ndufab1 effectively enhanced mitochondrial bioenergetics while limiting ROS production and protected the heart against ischemia-reperfusion injury. Together, our findings identify that NDUFAB1 is a crucial regulator of mitochondrial energy and ROS metabolism through coordinating the assembly of respiratory complexes and supercomplexes, and thus provide a potential therapeutic target for the prevention and treatment of heart failure.
  LETTERS TO THE EDITOR
Yifei Gao 1, Gaofeng Pei 1, Dongxue Li 1, Ru Li 1, Yanqiu Shao 2, Qiangfeng Cliff Zhang 2 and Pilong Li 1
https://doi.org/10.1038/s41422-019-0210-3
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Dear Editor,

Posttranscriptional modifications of coding and non-coding RNAs are prevalent in cells. N6-methyladenosine (m6A) is the most abundant type of modification on eukaryotic messenger RNAs (mRNAs).1 This modification plays important roles in multiple fundamental biological processes, for example, cell differentiation, tissue development and tumorigenesis.2,3 Like many other chemical modifications on biological macromolecules (proteins, DNAs, and RNAs), m6A can also be recognized by specific reader domains. The best-studied m6A reader domain is the YT521-B homology (YTH) domain, which is conserved from yeast to human and preferentially binds to a RR(m6A)CU (R = G or A) consensus motif.4,5,6,7 Humans have five proteins containing a YTH domain, of which three, YTHDF1-3, belong to the same protein family, the DF family.7 In addition to the well-folded YTH domain at their C-termini, all three proteins also have a low complexity domain (LCD) at their N-termini (Fig. 1a). Their LCD regions are predicted to be Prion-like domains (Fig. 1a). Prion-like domain-containing proteins often have the potential to undergo phase separation.8 Phase separation is often found to contribute to biomolecular condensation.9 Indeed, the LCDs of all three YTHDF proteins (Fig. S1) underwent concentration-dependent phase separation in the absence of RNA (Fig. 1b and S2). The resulting condensates exhibited liquid properties as two or more droplets can grow into a much larger droplet (Fig. S3a). Full-length YTHDF1/2/3 proteins (Fig. S1) also underwent phase separation under physiological conditions in the absence of RNA, although their capacity for phase separation was decreased in comparison with their LCDs (Fig. 1b and S3b).
Shuai Gao 1, Sujun Chen 2,3, Dong Han1, David Barrett1, Wanting Han 1, Musaddeque Ahmed3, Susan Patalano1, Jill A. Macoska1, Housheng Hansen He 2,3 and Changmeng Cai 1
https://doi.org/10.1038/s41422-019-0203-2
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Dear Editor,

FOXA1 (Forkhead Box Protein A1) is a pioneer transcription factor (TF) that functions to loosen the compact chromatin structure to facilitate binding of other TFs such as estrogen receptor and androgen receptor (AR).1,2 AR is a nuclear receptor functioning as a ligand-dependent TF that plays a pivotal role in driving the initiation of prostate cancer (PCa) and the development of castration-resistant PCa (CRPC).3 The chromatin binding of AR is dependent on FOXA1, which interacts with DNA through its Forkhead DNA binding domain (FKHD). Recent studies on PCa patient samples revealed genetic mutations of FOXA1 in primary PCa (~4%) and the mutation frequency is increased in the high-risk racial groups and in more aggressive metastatic CRPC (~10%),4,5,6,7 suggesting that PCa with FOXA1 mutations may be more aggressive and resistant to current therapies. The majority of FOXA1 mutations (~60%-80%) are found in a hot spot region located at the Wing2 region of FKHD. Due to a lack of functional studies, it remains unclear how these mutations affect PCa progression and patient outcome.
Bohan Xu1, Bing Song1, Xiaodong Lu1, Jung Kim1, Ming Hu2, Jonathan C. Zhao 1,3 and Jindan Yu 1,3,4
https://doi.org/10.1038/s41422-019-0204-1
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Dear Editor,

FOXA1, a forkhead (FKHD) family transcription factor, is highly expressed in the epithelium of endoderm-derived organs, including the prostate gland.1 Transgenic mouse studies have shown that FOXA1 expression is required for prostate epithelial cell differentiation and ductal morphogenesis during development and for the maintenance of this differentiated epithelial phenotype in the adult. Mechanistically, FOXA1 binds FKHD motifs in the DNA to open chromatin and increase local accessibility, thereby recruiting androgen receptor (AR) to prostate lineage-specific enhancers.2,3 AR mediates prostatic transcriptional program and normal prostate development and function. However, AR also plays a pivotal role in prostate cancer (PCa). Equilibrium between nuclear FOXA1 and AR levels is essential for defining a prostatic, rather than an oncogenic, AR program and for balancing cell differentiation and growth.4,5 In addition, FOXA1 has been shown to play androgen-independent roles in regulating epithelial-to-mesenchymal transition (EMT), cell invasion, and tumor metastasis.6 Recent studies have found FOXA1 among the most frequently mutated genes in PCa, with ~4% and ~12% mutation rates in localized tumors and metastatic castration-resistant prostate cancer (CRPC), respectively.7,8 A majority of these mutations cluster at the FKHD domain, especially around the Wing2 region.
  CORRIGENDA
Zhongzhong Chen 1,2, Yunping Lei 3,4, Yufang Zheng 1,2,5,Vanessa Aguiar-Pulido 6, M. Elizabeth Ross 6, Rui Peng 1, Li Jin 1,2,Ting Zhang 7, Richard H. Finnell 3,4 and Hongyan Wang 1,2,8,9
https://doi.org/10.1038/s41422-019-0201-4
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Correction to: Cell Research https://doi.org/10.1038/s41422-018-0061-3, published online 05 July 2018
Junya Peng1, Bao-Fa Sun 2,3,4, Chuan-Yuan Chen 2,3, Jia-Yi Zhou 2,3, Yu-Sheng Chen 2,3, Hao Chen5, Lulu Liu1, Dan Huang1, Jialin Jiang5,Guan-Shen Cui 2,3, Ying Yang 2,3,4, Wenze Wang6, Dan Guo 1,7, Menghua Dai5, Junchao Guo5, Taiping Zhang5, Quan Liao5, Yi Liu8, Yong-Liang Zhao 2,3,4, Da-Li Han 2,3,4, Yupei Zhao 5,8, Yun-Gui Yang 2,3,4 and Wenming Wu 5
https://doi.org/10.1038/s41422-019-0212-1
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Correction to: Cell Research (2019) https://doi.org/10.1038/s41422-019-0195-y, published online 4 July 2019
Shanhui Liao1 , Girish Rajendraprasad 2, Na Wang3, Susana Eibes2, Jun Gao1, Huijuan Yu1, Gao Wu1, Xiaoming Tu1, Hongda Huang3,Marin Barisic 2,4 and Chao Xu 1
https://doi.org/10.1038/s41422-019-0215-y
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Correction to: Cell Research https://doi.org/10.1038/s41422-019-0187-y, published online 6 June 2019
 

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