IU Indianapolis ScholarWorks :: Browsing by Author "Zhou, Bin"

Browsing by Author "Zhou, Bin"

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Author Correction: REST regulates the cell cycle for cardiac development and regeneration
(Springer Nature, 2018-01-12) Zhang, Donghong; Wang, Yidong; Lu, Pengfei; Wang, Ping; Yuan, Xinchun; Yan, Jianyun; Cai, Chenleng; Chang, Ching-Pin; Zheng, Deyou; Wu, Bingruo; Zhou, Bin; Medicine, School of Medicine
Despite the importance of cardiomyocyte proliferation in cardiac development and regeneration, the mechanisms that promote cardiomyocyte cell cycle remain incompletely understood. RE1 silencing transcription factor (REST) is a transcriptional repressor of neuronal genes. Here we show that REST also regulates the cardiomyocyte cell cycle. REST binds and represses the cell cycle inhibitor gene p21 and is required for mouse cardiac development and regeneration. Rest deletion de-represses p21 and inhibits the cardiomyocyte cell cycle and proliferation in embryonic or regenerating hearts. By contrast, REST overexpression in cultured cardiomyocytes represses p21 and increases proliferation. We further show that p21 knockout rescues cardiomyocyte cell cycle and proliferation defects resulting from Rest deletion. Our study reveals a REST-p21 regulatory axis as a mechanism for cell cycle progression in cardiomyocytes, which might be exploited therapeutically to enhance cardiac regeneration.
Biogenesis and molecular characteristics of serum hepatitis B virus RNA
(Public Library of Science, 2020-10-20) Shen, Sheng; Xie, Zhanglian; Cai, Dawei; Yu, Xiaoyang; Zhang, Hu; Kim, Elena S.; Zhou, Bin; Hou, Jinlin; Zhang, Xiaoyong; Huang, Qi; Sun, Jian; Guo, Haitao; Medicine, School of Medicine
HBV is an enveloped DNA virus that replicates its DNA genome via reverse transcription of a pregenomic (pg) RNA intermediate in hepatocytes. Interestingly, HBV RNA can be detected in virus-like particles in chronic hepatitis B (CHB) patient serum and has been utilized as a biomarker for intrahepatic cccDNA activity in treated patients. However, the biogenesis and molecular characteristics of serum HBV RNA remain to be fully defined. In this study, we found that the encapsidated serum HBV RNA predominately consists of pgRNA, which are detergent- and ribonuclease-resistant. Through blocking HBV DNA replication without affecting pgRNA encapsidation by using the priming-defective HBV mutant Y63D or 3TC treatment, we demonstrated that the cell culture supernatant contains a large amount of pgRNA-containing nonenveloped capsids and a minor population of pgRNA-containing virions. The formation of pgRNA-virion requires both capsid assembly and viral envelope proteins, which can be inhibited by capsid assembly modulators and an envelope–knockout mutant, respectively. Furthermore, the pgRNA-virion utilizes the multivesicular body pathway for egress, in a similar way as DNA-virion morphogenesis. Northern blotting, RT-PCR, and 3’ RACE assays revealed that serum/supernatant HBV pgRNA are mainly spliced and devoid of the 3’-terminal sequences. Furthermore, pgRNA-virion collected from cells treated with a reversible HBV priming inhibitor L-FMAU was unable to establish infection in HepG2-NTCP cells. In summary, serum HBV RNA is secreted in noninfectious virion-like particle as spliced and poly(A)-free pgRNA. Our study will shed light on the molecular biology of serum HBV RNA in HBV life cycle, and aid the development of serum HBV RNA as a novel biomarker for CHB diagnosis and treatment prognosis.
Epicardial calcineurin-NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development
(Oxford University Press, 2014-01-01) Yang, Jin; Zeini, Miriam; Lin, Chieh-Yu; Chieh-Yu, Chien-Jung; Xiong, Yiqin; Shang, Ching; Han, Pei; Li, Wei; Quertermous, Thomas; Zhou, Bin; Chang, Ching-Pin; Department of Medicine, IU School of Medicine
AIMS: Congenital coronary artery anomalies produce serious events that include syncope, arrhythmias, myocardial infarction, or sudden death. Studying the mechanism of coronary development will contribute to the understanding of the disease and help design new diagnostic or therapeutic strategies. Here, we characterized a new calcineurin-NFAT signalling which specifically functions in the epicardium to regulate the development of smooth muscle wall of the coronary arteries. METHODS AND RESULTS: Using tissue-specific gene deletion, we found that calcineurin-NFAT signals in the embryonic epicardium to direct coronary smooth muscle cell development. The smooth muscle wall of coronary arteries fails to mature in mice with epicardial deletion of calcineurin B1 (Cnb1), and accordingly these mutant mice develop cardiac dysfunction with reduced exercise capacity. Inhibition of calcineurin at various developmental windows shows that calcineurin-NFAT signals within a narrow time window at embryonic Day 12.5-13.5 to regulate coronary smooth muscle cell development. Within the epicardium, NFAT transcriptionally activates the expression of Smad2, whose gene product is critical for transducing transforming growth factor β (TGFβ)-Alk5 signalling to control coronary development. CONCLUSION: Our findings demonstrate new spatiotemporal and molecular actions of calcineurin-NFAT that dictate coronary arterial wall development and a new mechanism by which calcineurin-NFAT integrates with TGFβ signalling during embryonic development.
Hand2 is an essential regulator for two Notch-dependent functions within the embryonic endocardium
(Elsevier, 2014-12-24) VanDusen, Nathan J.; Casanovas, Jose; Vincentz, Joshua W.; Firulli, Beth A.; Osterwalder, Marco; Lopez-Rios, Javier; Zeller, Rolf; Zhou, Bin; Grego-Bessa, Joaquim; De La Pompa, José Luis; Shou, Weinian; Firulli, Anthony B.; Department of Pediatrics, IU School of Medicine
The basic-helix-loop-helix (bHLH) transcription factor Hand2 plays critical roles during cardiac morphogenesis via expression and function within myocardial, neural crest, and epicardial cell populations. Here, we show that Hand2 plays two essential Notch-dependent roles within the endocardium. Endocardial ablation of Hand2 results in failure to develop a patent tricuspid valve, intraventricular septum defects, and hypotrabeculated ventricles, which collectively resemble the human congenital defect tricuspid atresia. We show endocardial Hand2 to be an integral downstream component of a Notch endocardium-to-myocardium signaling pathway and a direct transcriptional regulator of Neuregulin1. Additionally, Hand2 participates in endocardium-to-endocardium-based cell signaling, with Hand2 mutant hearts displaying an increased density of coronary lumens. Molecular analyses further reveal dysregulation of several crucial components of Vegf signaling, including VegfA, VegfR2, Nrp1, and VegfR3. Thus, Hand2 functions as a crucial downstream transcriptional effector of endocardial Notch signaling during both cardiogenesis and coronary vasculogenesis.
A long non-coding RNA protects the heart from pathological hypertrophy
(Nature Publishing Group, 2014-10-02) Han, Pei; Li, Wei; Lin, Chiou-Hong; Yang, Jin; Shang, Ching; Nuernberg, Sylvia T.; Jin, Kevin Kai; Xu, Weihong; Lin, Chieh-Yu; Lin, Chien-Jung; Xiong, Yiqin; Chien, Huanchieh; Zhou, Bin; Ashley, Euan; Bernstein, Daniel; Chen, Peng-Sheng; Chen, Huei-sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin; Department of Medicine, IU School of Medicine
The role of long noncoding RNA (lncRNA) in adult hearts is unknown
Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification
(Nature Publishing Group, 2018-02-08) Miao, Lianjie; Li, Jingjing; Li, Jun; Tian, Xueying; Lu, Yangyang; Hu, Saiyang; Shieh, David; Kanai, Ryan; Zhou, Bo-yang; Zhou, Bin; Liu, Jiandong; Firulli, Anthony B.; Martin, James F.; Singer, Harold; Zhou, Bin; Xin, Hongbo; Wu, Mingfu; Pediatrics, School of Medicine
Hey2 gene mutations in both humans and mice have been associated with multiple cardiac defects. However, the currently reported localization of Hey2 in the ventricular compact zone cannot explain the wide variety of cardiac defects. Furthermore, it was reported that, in contrast to other organs, Notch doesn't regulate Hey2 in the heart. To determine the expression pattern and the regulation of Hey2, we used novel methods including RNAscope and a Hey2 CreERT2 knockin line to precisely determine the spatiotemporal expression pattern and level of Hey2 during cardiac development. We found that Hey2 is expressed in the endocardial cells of the atrioventricular canal and the outflow tract, as well as at the base of trabeculae, in addition to the reported expression in the ventricular compact myocardium. By disrupting several signaling pathways that regulate trabeculation and/or compaction, we found that, in contrast to previous reports, Notch signaling and Nrg1/ErbB2 regulate Hey2 expression level in myocardium and/or endocardium, but not its expression pattern: weak expression in trabecular myocardium and strong expression in compact myocardium. Instead, we found that FGF signaling regulates the expression pattern of Hey2 in the early myocardium, and regulates the expression level of Hey2 in a Notch1 dependent manner.
Rapid Turnover of Hepatitis B Virus Covalently Closed Circular DNA Indicated by Monitoring Emergence and Reversion of Signature-Mutation in Treated Chronic Hepatitis B Patients
(Wiley, 2021) Huang, Qi; Zhou, Bin; Cai, Dawei; Zong, Yuhua; Wu, Yaobo; Liu, Shi; Mercier, Alexandre; Guo, Haitao; Hou, Jinlin; Colonno, Richard; Sun, Jian; Microbiology and Immunology, School of Medicine
Background and aims: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a pivotal role in the establishment and persistence of HBV infection. Understanding the turnover time of preexisting cccDNA pools would be helpful in designing strategies to clear HBV by fully blocking the de novo generation of cccDNA. Approach and results: In this study, we retrospectively monitored the emergence and reversion of the rtM204I/V mutant, a signature lamivudine resistance (LAMR ) mutation serving as a biomarker of cccDNA turnover in liver biopsies and longitudinal serum samples from two clinical trials. Methodologies were optimized to differentially isolate and sequence HBV virion DNA, cccDNA, and HBV RNA from clinical samples. A strong correlation was observed between LAMR composition of cccDNA with that of serum and intrahepatic HBV RNA in paired liver and serum samples (r = 0.96 and 0.90, respectively), suggesting that serum HBV RNA can serve as a surrogate marker of cccDNA genetic composition when liver biopsies are unavailable. LAMR mutations emerged and increased from undetectable to 40%-90% within 16-28 weeks in serum HBV RNA from telbivudine-treated patients experiencing virological breakthrough. Similarly, in lamivudine-resistant patients who switched to interferon therapy, serum HBV-RNA population bearing 100% LAMR mutations fully reversed back to wild type within 24-48 weeks. Conclusions: The genetic composition dynamics of serum HBV RNA and biopsy cccDNA in treated HBV patients indicates that cccDNA turnover occurs relatively rapidly (several months), offering a possibility of HBV cure with finite therapy through completely blocking cccDNA replenishment.
REST regulates the cell cycle for cardiac development and regeneration
(Nature Publishing group, 2017-12-07) Zhang, Donghong; Wang, Yidong; Lu, Pengfei; Wang, Ping; Yuan, Xinchun; Yan, Jianyun; Cai, Chenleng; Chang, Ching-Pin; Zheng, Deyou; Wu, Bingruo; Zhou, Bin; Medicine, School of Medicine
Despite the importance of cardiomyocyte proliferation in cardiac development and regeneration, the mechanisms that promote cardiomyocyte cell cycle remain incompletely understood. RE1 silencing transcription factor (REST) is a transcriptional repressor of neuronal genes. Here we show that REST also regulates the cardiomyocyte cell cycle. REST binds and represses the cell cycle inhibitor gene p21 and is required for mouse cardiac development and regeneration. Rest deletion de-represses p21 and inhibits the cardiomyocyte cell cycle and proliferation in embryonic or regenerating hearts. By contrast, REST overexpression in cultured cardiomyocytes represses p21 and increases proliferation. We further show that p21 knockout rescues cardiomyocyte cell cycle and proliferation defects resulting from Rest deletion. Our study reveals a REST-p21 regulatory axis as a mechanism for cell cycle progression in cardiomyocytes, which might be exploited therapeutically to enhance cardiac regeneration., The mechanisms regulating cardiomyocyte proliferation during development and cardiac regeneration are incompletely understood. The authors show that the transcription factor REST regulates cardiomyocyte proliferation by binding and repressing the cell cycle inhibitor p21.
Retraction Note: REST regulates the cell cycle for cardiac development and regeneration
(Springer Nature, 2024-02-22) Zhang, Donghong; Wang, Yidong; Lu, Pengfei; Wang, Ping; Yuan, Xinchun; Yan, Jianyun; Cai, Chenleng; Chang, Ching-Pin; Zheng, Deyou; Wu, Bingruo; Zhou, Bin; Medicine, School of Medicine
Retraction to: Nature Communications 10.1038/s41467-017-02210-y, published online 07 December 2017 The authors have retracted this article because of significant concerns regarding a number of figures presented in this work that question the integrity of the data. After publication, several concerns were raised about the figures in this article. Specifically, * There appears to be a partial overlap between two panels of Figure 4e (bottom left corner for p21KO and top right for DKO). * There appears to be an overlap between a control panel from figure 2k and Rest imKO in Figure 5g (PH3 staining). * There appears to be image reuse between two samples in Figure 5g in the Aurora B staining row for Rest imKO and p21KO. * There appears to be an overlap between Figure 6f Ph3 staining for the Rest cDNA sample and Supplementary Fig. 6e, EdU staining, Rest cDNA, with fewer arrows and less visible DAPI staining. All authors agree with this retraction.
Serum HBV RNA: a New Potential Biomarker for Chronic Hepatitis B Virus Infection
(AASLD, 2018) Liu, Shi; Zhou, Bin; Valdes, Juan D.; Sun, Jian; Guo, Haitao; Microbiology and Immunology, School of Medicine
Chronic hepatitis B (CHB) is one of the major etiological causes of liver failure, cirrhosis, and hepatocellular carcinoma worldwide, and it cannot be completely cured by currently available drugs due to the persistent existence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the bona fide transcription template for HBV RNAs, in the infected hepatocytes. Since quantifying cccDNA per se requires an invasive procedure, serum biomarkers reflecting the intrahepatic cccDNA activity are warranted. Recently, a growing body of research suggests that the circulating HBV RNA may serve as a new serum biomarker for HBV infection, treatment and prognosis. In order to delineate the molecular and clinical characteristics of serum HBV RNA, we systematically reviewed the available literature on serum HBV RNA dating back to early 1990s. In this review, we will summarize the reported serum HBV RNA quantification methods and discuss the potential HBV RNA species in patient serum, and compare the reported correlations of serum HBV RNA with other serological markers, including HBV DNA, hepatitis B surface antigen (HBsAg), e antigen (HBeAg), and core‐related antigen (HBcrAg), as well as their correlations with the intrahepatic cccDNA, to assess its potential in clinical applications. The future directions for serum HBV RNA research will also be discussed.

Browsing by Author "Zhou, Bin"

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