Browsing by Author "Wang, Feng"
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Item 5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer’s disease(Cell Press, 2021-04-27) Kuehner, Janise N.; Chen, Junyu; Bruggeman, Emily C.; Wang, Feng; Li, Yangping; Xu, Chongchong; McEachin, Zachary T.; Li, Ziyi; Chen, Li; Hales, Chadwick M.; Wen, Zhexing; Yang, Jingjing; Yao, Bing; Medicine, School of Medicine5-hydroxymethylcytosine (5hmC) undergoes dynamic changes during mammalian brain development, and its dysregulation is associated with Alzheimer's disease (AD). The dynamics of 5hmC during early human brain development and how they contribute to AD pathologies remain largely unexplored. We generate 5hmC and transcriptome profiles encompassing several developmental time points of healthy forebrain organoids and organoids derived from several familial AD patients. Stage-specific differentially hydroxymethylated regions demonstrate an acquisition or depletion of 5hmC modifications across developmental stages. Additionally, genes concomitantly increasing or decreasing in 5hmC and gene expression are enriched in neurobiological or early developmental processes, respectively. Importantly, our AD organoids corroborate cellular and molecular phenotypes previously observed in human AD brains. 5hmC is significantly altered in developmentally programmed 5hmC intragenic regions in defined fetal histone marks and enhancers in AD organoids. These data suggest a highly coordinated molecular system that may be dysregulated in these early developing AD organoids.Item Accurate identification of circRNA landscape and complexity reveals their pivotal roles in human oligodendroglia differentiation(BMC, 2022-02-07) Li, Yangping; Wang, Feng; Teng, Peng; Ku, Li; Chen, Li; Feng, Yue; Yao, Bing; Biostatistics and Health Data Science, School of MedicineBackground: Circular RNAs (circRNAs), a novel class of poorly conserved non-coding RNAs that regulate gene expression, are highly enriched in the human brain. Despite increasing discoveries of circRNA function in human neurons, the circRNA landscape and function in developing human oligodendroglia, the myelinating cells that govern neuronal conductance, remains unexplored. Meanwhile, improved experimental and computational tools for the accurate identification of circRNAs are needed. Results: We adopt a published experimental approach for circRNA enrichment and develop CARP (CircRNA identification using A-tailing RNase R approach and Pseudo-reference alignment), a comprehensive 21-module computational framework for accurate circRNA identification and quantification. Using CARP, we identify developmentally programmed human oligodendroglia circRNA landscapes in the HOG oligodendroglioma cell line, distinct from neuronal circRNA landscapes. Numerous circRNAs display oligodendroglia-specific regulation upon differentiation, among which a subclass is regulated independently from their parental mRNAs. We find that circRNA flanking introns often contain cis-regulatory elements for RNA editing and are predicted to bind differentiation-regulated splicing factors. In addition, we discover novel oligodendroglia-specific circRNAs that are predicted to sponge microRNAs, which co-operatively promote oligodendroglia development. Furthermore, we identify circRNA clusters derived from differentiation-regulated alternative circularization events within the same gene, each containing a common circular exon, achieving additive sponging effects that promote human oligodendroglia differentiation. Conclusions: Our results reveal dynamic regulation of human oligodendroglia circRNA landscapes during early differentiation and suggest critical roles of the circRNA-miRNA-mRNA axis in advancing human oligodendroglia development.Item Assembly of a dsRNA synthesizing complex: RNA-DEPENDENT RNA POLYMERASE 2 contacts the largest subunit of NUCLEAR RNA POLYMERASE IV(National Academy of Sciences, 2021-03-30) Mishra, Vibhor; Singh, Jasleen; Wang, Feng; Zhang, Yixiang; Fukudome, Akihito; Trinidad, Jonathan C.; Takagi, Yuichiro; Pikaard, Craig S.; Biochemistry and Molecular Biology, School of MedicineIn plants, transcription of selfish genetic elements such as transposons and DNA viruses is suppressed by RNA-directed DNA methylation. This process is guided by 24-nt short-interfering RNAs (siRNAs) whose double-stranded precursors are synthesized by DNA-dependent NUCLEAR RNA POLYMERASE IV (Pol IV) and RNA-DEPENDENT RNA POLYMERASE 2 (RDR2). Pol IV and RDR2 coimmunoprecipitate, and their activities are tightly coupled, yet the basis for their association is unknown. Here, we show that an interval near the RDR2 active site contacts the Pol IV catalytic subunit, NRPD1, the largest of Pol IV's 12 subunits. Contacts between the catalytic regions of the two enzymes suggests that RDR2 is positioned to rapidly engage the free 3' ends of Pol IV transcripts and convert these single-stranded transcripts into double-stranded RNAs (dsRNAs).Item Belantamab mafodotin for the treatment of relapsed/refractory multiple myeloma in heavily pretreated patients: a US cost-effectiveness analysis(Taylor & Francis, 2021) Nikolaou, Andreas; Ambavane, Apoorva; Shah, Anshul; Ma, Wenkang; Tosh, Jon; Kapetanakis, Venediktos; Willson, Jenny; Wang, Feng; Hogea, Cosmina; Gorsh, Boris; Gutierrez, Ben; Sapra, Sandhya; Suvannasankha, Attaya; Samyshkin, Yevgeniy; Medicine, School of MedicineBackground: Patients with relapsed/refractory multiple myeloma (RRMM) require several lines of therapy, with typically shorter remission duration with each additional line. Research design and methods: The cost-effectiveness of belantamab mafodotin (belamaf; DREAMM-2; NCT03525678) was compared with selinexor plus dexamethasone (SEL+DEX; STORM Part 2; NCT02336815) among patients with RRMM who have received at least four prior therapies. The base case used a US commercial payer's perspective over a 10-year time horizon. Efficacy data were based on parametric survival analysis of DREAMM-2 and matching-adjusted indirect treatment comparison between DREAMM-2 and STORM Part 2, which assessed relative treatment effects between belamaf and SEL+DEX. Cost inputs included drug treatment, concomitant medications, adverse event management, subsequent treatments, and disease management. Results: Belamaf decreased total treatment costs per patient by $14,267 and increased patient life years by 0.74 and quality-adjusted life years (QALYs) by 0.49 versus SEL+DEX. Patients receiving belamaf accrued 0.12 fewer progression-free life years versus patients on SEL+DEX. Conclusions: From a US commercial payer's perspective, belamaf had lower costs, and increased QALYs and life-year gain, compared with SEL+DEX. Belamaf is therefore likely to be a cost-effective treatment option for patients with RRMM who have received four or more prior lines of therapy.Item circMeta: a unified computational framework for genomic feature annotation and differential expression analysis of circular RNAs(Oxford University Press, 2020-01-15) Chen, Li; Wang, Feng; Bruggeman, Emily C.; Li, Chao; Yao, Bing; Medicine, School of MedicineMotivation: Circular RNAs (circRNAs), a class of non-coding RNAs generated from non-canonical back-splicing events, have emerged to play key roles in many biological processes. Though numerous tools have been developed to detect circRNAs from rRNA-depleted RNA-seq data based on back-splicing junction-spanning reads, computational tools to identify critical genomic features regulating circRNA biogenesis are still lacking. In addition, rigorous statistical methods to perform differential expression (DE) analysis of circRNAs remain under-developed. Results: We present circMeta, a unified computational framework for circRNA analyses. circMeta has three primary functional modules: (i) a pipeline for comprehensive genomic feature annotation related to circRNA biogenesis, including length of introns flanking circularized exons, repetitive elements such as Alu elements and SINEs, competition score for forming circulation and RNA editing in back-splicing flanking introns; (ii) a two-stage DE approach of circRNAs based on circular junction reads to quantitatively compare circRNA levels and (iii) a Bayesian hierarchical model for DE analysis of circRNAs based on the ratio of circular reads to linear reads in back-splicing sites to study spatial and temporal regulation of circRNA production. Both proposed DE methods without and with considering host genes outperform existing methods by obtaining better control of false discovery rate and comparable statistical power. Moreover, the identified DE circRNAs by the proposed two-stage DE approach display potential biological functions in Gene Ontology and circRNA-miRNA-mRNA networks that are not able to be detected using existing mRNA DE methods. Furthermore, top DE circRNAs have been further validated by RT-qPCR using divergent primers spanning back-splicing junctions.Item Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity(Elsevier, 2019-03-12) Aho, Erin R.; Wang, Jing; Gogliotti, Rocco D.; Howard, Gregory C.; Phan, Jason; Acharya, Pankaj; Macdonald, Jonathan D.; Cheng, Ken; Lorey, Shelly L.; Lu, Bin; Wenzel, Sabine; Foshage, Audra M.; Alvarado, Joseph; Wang, Feng; Shaw, J. Grace; Zhao, Bin; Weissmiller, April M.; Thomas, Lance R.; Vakoc, Christopher R.; Hall, Matthew D.; Hiebert, Scott W.; Liu, Qi; Stauffer, Shaun R.; Fesik, Stephen W.; Tansey, William P.; Biochemistry and Molecular Biology, School of MedicineThe chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.Item DREAMM-2: Indirect Comparisons of Belantamab Mafodotin vs. Selinexor + Dexamethasone and Standard of Care Treatments in Relapsed/Refractory Multiple Myeloma(Springer, 2021) Prawitz, Thibaud; Popat, Rakesh; Suvannasankha, Attaya; Sarri, Grammati; Hughes, Rachel; Wang, Feng; Hogea, Cosmina; Ferrante, Shannon Allen; Gorsh, Boris; Willson, Jenny; Kapetanakis, Venediktos; Medicine, School of MedicineIntroduction: Single-agent belantamab mafodotin (belamaf; BLENREP) demonstrated deep and durable responses in patients with relapsed/refractory multiple myeloma and ≥ 3 prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody (DREAMM-2; NCT03525678). Methods: At the time of this study, STORM Part 2, NCT02336815 (selinexor plus low-dose dexamethasone; sel + dex) was systematically identified as the only feasible comparator to the DREAMM-2 cohort. Matching-adjusted indirect comparisons (MAIC) evaluated efficacy and safety of belamaf (2.5 mg/kg; n = 97) versus sel + dex (80 mg + 20 mg, respectively; n = 123). Populations were weighted for clinically validated effect modifiers and prognostic factors. Outcomes included overall survival (OS), progression-free survival (PFS), duration of response (DoR), overall response rate (ORR), time to response (TTR), and safety. The relative efficacy of belamaf versus standard of care (SoC) on OS was estimated by a Bucher indirect treatment comparison using the MAIC-adjusted hazard ratios (HR) for OS of belamaf (DREAMM-2) versus sel + dex (STORM Part 2) and a HR adjusted for refractoriness to carfilzomib and high-risk cytogenetics of sel + dex (STORM) versus SoC (MAMMOTH). Results: Belamaf demonstrated improved OS (HR 0.53; 95% confidence interval 0.34, 0.83; p = 0.005) and DoR (0.41; 0.21, 0.83; p = 0.013) versus sel + dex. There were no statistically significant differences in ORR, TTR, and PFS. Belamaf had a favorable safety profile for most evaluable hematologic (any-grade, Grade 3-4) and non-hematologic (any-grade) adverse events versus sel + dex. Significantly improved OS was observed with belamaf versus SoC (0.29; 0.16, 0.54; p < 0.001). Conclusion: Single-agent belamaf represents a new treatment option for triple-class refractory patients with RRMM.Item Ionic liquid-assisted synthesis of Yb3+-Tm3+ codoped Y7O6F9 petal shaped microcrystals with enhanced upconversion emission(Elsevier, 2018-07) Zhao, Jinbo; Wu, Lili; Zhang, Chuanjiang; Li, Tingxi; Jiang, Qinglong; Wang, Feng; Zhao, Ping; Ryu, Jong Eun; Guo, Zhanhu; Mechanical Engineering, School of Engineering and TechnologyPetal-like Yb3+-Tm3+ codoped Y7O6F9 microparticles were achieved via ionic liquid-assisted (IL) hydrothermal process. The emission efficiency of Y7O6F9:Yb3+/Tm3+ powders is much stronger than that of Y2O3:Yb3+/Tm3+ sample. Under excitation at 980 nm with an unfocused laser beam under weak pump density of ∼0.1 W/cm2 (pump power 10 mW), the UC emission of the sample can been seen clearly. Four emission bands at 477, 540, 647 and 692 nm are observed and correspond to the 1G4 state to 3H6 state, 1D2 state to 3H5 state, 1G4 sate to 3F4 state, and 3F3 state to 3H6 state transition of Tm3+ ions. The enhanced UC emission is related to high crystallinity and lower effective phonon energy of oxyfluorides. The ionic liquid (IL) of [BMIM][BF4] is used both as the reaction medium and the source of F−.Item Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet(Elsevier, 2019-11) Luo, Yongde; Yang, Yaying; Liu, Muyun; Wang, Dan; Wang, Feng; Bi, Yawei; Ji, Juntao; Li, Suyun; Liu, Yan; Chen, Rong; Huang, Haojie; Wang, Xiaojie; Swidnicka-Siergiejko, Agnieszka K.; Janowitz, Tobias; Beyaz, Semir; Wang, Guoqiang; Xu, Sulan; Bialkowska, Agnieszka B.; Luo, Catherine K.; Pin, Christoph L.; Liang, Guang; Lu, Xiongbin; Wu, Maoxin; Shroyer, Kenneth R.; Wolff, Robert A.; Plunkett, William; Ji, Baoan; Li, Zhaoshen; Li, Ellen; Li, Xiaokun; Yang, Vincent W.; Logsdon, Craig D.; Abbruzzese, James L.; Lu, Weiqin; Medical and Molecular Genetics, School of MedicineBackground & Aims Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. Methods We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. Results Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression—a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival—only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. Conclusions Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.Item Weighted Gene Co-expression Network Analysis for RNA-Sequencing Data of the Varicose Veins Transcriptome(Frontiers, 2019-03-19) Zhang, Jianbin; Nie, Qiangqiang; Si, Chaozeng; Wang, Cheng; Chen, Yang; Sun, Weiliang; Pan, Lin; Guo, Jing; Kong, Jie; Cui, Yiyao; Wang, Feng; Fan, Xueqiang; Ye, Zhidong; Wen, Jianyan; Liu, Peng; Medicine, School of MedicineObjective: Varicose veins are a common problem worldwide and can cause significant impairments in health-related quality of life, but the etiology and pathogenesis remain not well defined. This study aims to elucidate transcriptomic regulations of varicose veins by detecting differentially expressed genes, pathways and regulator genes. Methods: We harvested great saphenous veins (GSV) from patients who underwent coronary artery bypass grafting (CABG) and varicose veins from conventional stripping surgery. RNA-Sequencing (RNA-Seq) technique was used to obtain the complete transcriptomic data of both GSVs from CABG patients and varicose veins. Weighted Gene Co-expression network analysis (WGCNA) and further analyses were then carried out with the aim to elucidate transcriptomic regulations of varicose veins by detecting differentially expressed genes, pathways and regulator genes. Results: From January 2015 to December 2016, 7 GSVs from CABG patients and 13 varicose veins were obtained. WGCNA identified 4 modules. In the brown module, gene ontology (GO) analysis showed that the biological processes were focused on response to stimulus, immune response and inflammatory response, etc. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis showed that the biological processes were focused on cytokine-cytokine receptor interaction and TNF signaling pathway, etc. In the gray module, GO analysis showed that the biological processes were skeletal myofibril assembly related. The immunohistochemistry staining showed that the expression of ASC, Caspase-1 and NLRP3 were increased in GSVs from CABG patients compared with varicose veins. Histopathological analysis showed that in the varicose veins group, the thickness of vascular wall, tunica intima, tunica media and collagen/smooth muscle ratio were significantly increased, and that the elastic fiber/internal elastic lamina ratio was decreased. Conclusion: This study shows that there are clear differences in transcriptomic information between varicose veins and GSVs from CABG patients. Some inflammatory RNAs are down-regulated in varicose veins compared with GSVs from CABG patients. Skeletal myofibril assembly pathway may play a crucial role in the pathogenesis of varicose veins. Characterization of these RNAs may provide new targets for understanding varicose veins diagnosis, progression, and treatment.