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Dive into the research topics where Benyu Liu is active.

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Featured researches published by Benyu Liu.


Nature Communications | 2016

LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells

Pingping Zhu; Yanying Wang; Jiayi Wu; Guanling Huang; Benyu Liu; Buqing Ye; Ying Du; Guangxia Gao; Yong Tian; Lei He; Zusen Fan

Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC). However, the biology of hepatic CSCs remains largely undefined. Through analysis of transcriptome microarray data, we identify a long noncoding RNA (lncRNA) called lncBRM, which is highly expressed in liver CSCs and HCC tumours. LncBRM is required for the self-renewal maintenance of liver CSCs and tumour initiation. In liver CSCs, lncBRM associates with BRM to initiate the BRG1/BRM switch and the BRG1-embedded BAF complex triggers activation of YAP1 signalling. Moreover, expression levels of lncBRM together with YAP1 signalling targets are positively correlated with tumour severity of HCC patients. Therefore, lncBRM and YAP1 signalling may serve as biomarkers for diagnosis and potential drug targets for HCC.


Nature Structural & Molecular Biology | 2016

lnc-β-Catm elicits EZH2-dependent β-catenin stabilization and sustains liver CSC self-renewal

Pingping Zhu; Yanying Wang; Guanling Huang; Buqing Ye; Benyu Liu; Jiayi Wu; Ying Du; Lei He; Zusen Fan

Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC); however, the molecular mechanisms underlying their self-renewal and differentiation remain largely unknown. Through analysis of transcriptome microarray data, we identified a long noncoding RNA (lncRNA) called lnc-β-Catm, which is highly expressed in human HCC tumors and liver CSCs. We found that lnc-β-Catm is required for self-renewal of liver CSCs and tumor propagation in mice. lnc-β-Catm associates with β-catenin and the methyltransferase EZH2, thereby promoting β-catenin methylation. Methylation suppresses the ubiquitination of β-catenin and promotes its stability, thus leading to activation of Wnt–β-catenin signaling. Accordingly, the expression of lnc-β-Catm, EZH2 and Wnt–β-catenin targets is positively correlated with cancer severity and prognosis of people with HCC.


Nature Immunology | 2017

Long noncoding RNA lncKdm2b is required for ILC3 maintenance by initiation of Zfp292 expression

Benyu Liu; Buqing Ye; Liuliu Yang; Xiaoxiao Zhu; Guanling Huang; Pingping Zhu; Ying Du; Jiayi Wu; Xiwen Qin; Runsheng Chen; Yong Tian; Zusen Fan

Innate lymphoid cells (ILCs) communicate with other hematopoietic and nonhematopoietic cells to regulate immunity, inflammation and tissue homeostasis. How ILC lineages develop and are maintained remains largely unknown. In this study we observed that a divergent long noncoding RNA (lncRNA), lncKdm2b, was expressed at high levels in intestinal group 3 ILCs (ILC3s). LncKdm2b deficiency in the hematopoietic system led to reductions in the number and effector functions of ILC3s. LncKdm2b expression sustained the maintenance of ILC3s by promoting their proliferation through activation of the transcription factor Zfp292. Mechanistically, lncKdm2b recruited the chromatin organizer Satb1 and the nuclear remodeling factor (NURF) complex onto the Zfp292 promoter to initiate its transcription. Deletion of Zfp292 or Bptf also abrogated the maintenance of ILC3s, leading to susceptibility to bacterial infection. Therefore, our findings reveal that lncRNAs may represent an additional layer of regulation of ILC development and function.


Journal of Experimental Medicine | 2014

Cytosolic carboxypeptidase CCP6 is required for megakaryopoiesis by modulating Mad2 polyglutamylation

Buqing Ye; Chong Li; Zhao Yang; Yanying Wang; Junfeng Hao; Li Wang; Yi Li; Ying Du; Lu Hao; Benyu Liu; Shuo Wang; Pengyan Xia; Guanling Huang; Lei Sun; Yong Tian; Zusen Fan

Ye et al. identify cytosolic carboxypeptidase CCP6 as a protein required for the regulation of bone marrow megakaryopoiesis in mice. The authors find that Mad2 (a core component of spindle checkpoint in mitosis) is a substrate of CCP6 in megakaryocytes and is polyglutamylated by proteins TTLL6 and TTLL4, subsequently affecting the activity of Aurora B kinase. Mad2 is thus additionally implicated in megakaryopoiesis regulation.


Stem Cells | 2014

Pcid2 inactivates developmental genes in human and mouse embryonic stem cells to sustain their pluripotency by modulation of EID1 stability

Buqing Ye; Zhonghua Dai; Benyu Liu; Rui Wang; Chong Li; Guanling Huang; Shuo Wang; Pengyan Xia; Xuan Yang; Kazuhiko Kuwahara; Nobuo Sakaguchi; Zusen Fan

Self‐renewal and differentiation are the hallmarks of embryonic stem cells (ESCs). However, it is largely unknown about how the pluripotency is regulated. Here we demonstrate that Pcid2 is required for the maintenance of self‐renewal both in mouse and human ESCs. Pcid2 plays a critical role in suppression of ESC differentiation. Pcid2 deficiency causes early embryonic lethality before the blastocyst stage. Pcid2 associates with EID1 and is present in the CBP/p300‐EID1 complex in the ESCs. We show that MDM2 is an E3 ligase for K48‐linked EID1 ubiquitination for its degradation. For the maintenance of self‐renewal, Pcid2 binds to EID1 to impede the association with MDM2. Then EID1 is not degraded to sustain its stability to block the HAT activity of CBP/p300, leading to suppression of the developmental gene expression. Collectively, Pcid2 is present in the CBP/p300‐EID1 complex to control the switch balance of mouse and human ESCs through modulation of EID1 degradation. Stem Cells 2014;32:623–635


Cancer Research | 2017

Mesenchymal Stem Cells Promote Hepatocarcinogenesis via lncRNA–MUF Interaction with ANXA2 and miR-34a

Xinlong Yan; Dongdong Zhang; Wei Wu; Shuheng Wu; Jingfeng Qian; Yajing Hao; Fang Yan; Pingping Zhu; Jiayi Wu; Guanling Huang; Yinghui Huang; Jianjun Luo; Xinhui Liu; Benyu Liu; Xiaomin Chen; Ying Du; Runsheng Chen; Zusen Fan

Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial-mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA-MUF (MSC-upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA-MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA-MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA-MUF bound Annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA-mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting. Cancer Res; 77(23); 6704-16. ©2017 AACR.


Journal of Immunology | 2015

The Endoplasmic Reticulum Adaptor Protein ERAdP Initiates NK Cell Activation via the Ubc13-Mediated NF-κB Pathway

Jun Chen; Lu Hao; Chong Li; Buqing Ye; Ying Du; Honglian Zhang; Bo Long; Pingping Zhu; Benyu Liu; Liuliu Yang; Peifeng Li; Yong Tian; Zusen Fan

NK cells play a pivotal role in innate immune responses against pathogenic infections. However, the underlying mechanisms driving defined NK functions remain largely elusive. In this study, we identified a novel endoplasmic reticulum (ER) membrane protein, ER adaptor protein (ERAdP), which is constitutively expressed in human and mouse NK cells. ERAdP is expressed at low levels in peripheral NK cells of hepatitis B virus–associated hepatocellular carcinoma patients. We show that ERAdP initiates NK cell activation through the NF-κB pathway. Notably, ERAdP interacts with ubiquitin-conjugating enzyme 13 (Ubc13) to potentiate its charging activity. Thus, ERAdP augments Ubc13-mediated NF-κB essential modulator ubiquitination to trigger the Ubc13-mediated NF-κB pathway, leading to NK cell activation. Finally, ERAdP transgenic mice display hyperactivated NK cells that are more resistant to pathogenic infections. Therefore, understanding the mechanism of ERAdP-mediated NK cell activation will provide strategies for treatment of infectious diseases.


The EMBO Journal | 2018

LncKdm2b controls self‐renewal of embryonic stem cells via activating expression of transcription factor Zbtb3

Buqing Ye; Benyu Liu; Liuliu Yang; Xiaoxiao Zhu; Dongdong Zhang; Wei Wu; Pingping Zhu; Yanying Wang; Shuo Wang; Pengyan Xia; Ying Du; Shu Meng; Guanling Huang; Jiayi Wu; Runsheng Chen; Yong Tian; Zusen Fan

Divergent long noncoding RNAs (lncRNAs) represent a major lncRNA biotype in mouse and human genomes. The biological and molecular functions of the divergent lncRNAs remain largely unknown. Here, we show that lncKdm2b, a divergent lncRNA for Kdm2b gene, is conserved among five mammalian species and highly expressed in embryonic stem cells (ESCs) and early embryos. LncKdm2b knockout impairs ESC self‐renewal and causes early embryonic lethality. LncKdm2b can activate Zbtb3 by promoting the assembly and ATPase activity of Snf2‐related CREBBP activator protein (SRCAP) complex in trans. Zbtb3 potentiates the ESC self‐renewal in a Nanog‐dependent manner. Finally, Zbtb3 deficiency impairs the ESC self‐renewal and early embryonic development. Therefore, our findings reveal that lncRNAs may represent an additional layer of the regulation of ESC self‐renewal and early embryogenesis.


Nature Communications | 2017

IL-7Rα glutamylation and activation of transcription factor Sall3 promote group 3 ILC development

Benyu Liu; Buqing Ye; Xiaoxiao Zhu; Guanling Huang; Liuliu Yang; Pingping Zhu; Ying Du; Jiayi Wu; Shu Meng; Yong Tian; Zusen Fan

Group 3 innate lymphoid cells (ILC3) promote lymphoid organogenesis and potentiate immune responses against bacterial infection. However, how ILC3 cells are developed and maintained is still unclear. Here, we show that carboxypeptidase CCP2 is highly expressed in common helper-like innate lymphoid progenitors, the progenitor of innate lymphoid cells, and CCP2 deficiency increases ILC3 numbers. Interleukin-7 receptor subunit alpha (IL-7Rα) is identified as a substrate of CCP2 for deglutamylation, and IL-7Rα polyglutamylation is catalyzed by polyglutamylases TTLL4 and TTLL13 in common helper-like innate lymphoid progenitors. IL-7Rα polyglutamylation triggers STAT5 activation to initiate transcription factor Sall3 expression in common helper-like innate lymphoid progenitors, which drives ILC3 cell differentiation. Moreover, Ttll4−/− or Ttll13−/− mice have reduced IL-7Rα polyglutamylation and Sall3 expression in common helper-like innate lymphoid progenitors. Importantly, mice with IL-7Rα E446A mutation have reduced Sall3 expression and ILC3 population. Thus, polyglutamylation and deglutamylation of IL-7Rα tightly controls the development and effector functions of ILC3s.Innate lymphoid cells (ILC) are important regulators of mucosal immunity, but how their development and homeostasis are modulated is still unclear. Here the authors show that the differentiation of group 3 ILCs is controlled by the glutamylation of IL-7Rα and the induction of transcription factor Sall3.


Nature Cell Biology | 2018

LncGata6 maintains stemness of intestinal stem cells and promotes intestinal tumorigenesis

Pingping Zhu; Jiayi Wu; Yanying Wang; Xiaoxiao Zhu; Tiankun Lu; Benyu Liu; Luyun He; Buqing Ye; Shuo Wang; Shu Meng; Dongdong Fan; Jing Wang; Liuliu Yang; Xiwen Qin; Ying Du; Chong Li; Lei He; Weizheng Ren; Xin Wu; Yong Tian; Zusen Fan

The intestinal epithelium harbours remarkable self-renewal capacity that is driven by Lgr5+ intestinal stem cells (ISCs) at the crypt base. However, the molecular mechanism controlling Lgr5+ ISC stemness is incompletely understood. We show that a Gata6 long noncoding RNA (lncGata6) is highly expressed in ISCs. LncGata6 knockout or conditional knockout in ISCs impairs the stemness of ISCs and epithelial regeneration. Mechanistically, lncGata6 recruits the NURF complex onto the Ehf promoter to induce its transcription, which promotes the expression of Lgr4/5 to enhance Wnt signalling activation. Moreover, the human orthologue lncGATA6 is highly expressed in the cancer stem cells of colorectal cancer and promotes tumour initiation and progression. Antisense oligonucleotides against lncGATA6 exhibit strong therapeutic efficacy on colorectal cancer. Thus, targeting lncGATA6 will have potential clinical applications in colorectal cancer treatment as an ideal therapeutic target.Zhu et al. show that the long noncoding RNA lncGata6 enhances Wnt signalling in intestinal stem cells by recruiting the NURF remodelling complex onto the Ehf promoter and initiating its transcription, which triggers expression of Lgr4/5.

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Zusen Fan

Chinese Academy of Sciences

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Buqing Ye

Chinese Academy of Sciences

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Ying Du

Chinese Academy of Sciences

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Guanling Huang

Chinese Academy of Sciences

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Pingping Zhu

Chinese Academy of Sciences

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Jiayi Wu

Chinese Academy of Sciences

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Yong Tian

Chinese Academy of Sciences

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Liuliu Yang

Chinese Academy of Sciences

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Shuo Wang

Chinese Academy of Sciences

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Yanying Wang

Chinese Academy of Sciences

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