Browsing by Author "Chen, Li"

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    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 Medicine
    5-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.
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    A case report of the metagenomics next-generation sequencing for early detection of central nervous system mucormycosis with successful rescue in patient with recurrent chronic lymphocytic leukemia
    (AME, 2022) Zhang, Jiaojiao; Luo, Jing; Weng, Xiangqin; Zhu, Yongmei; Goyal, Gaurav; Perna, Fabiana; Espinoza-Gutarra, Manuel; Jiang, Lu; Chen, Li; Mi, Jian-Qing; Medicine, School of Medicine
    Background: Central nervous system (CNS) mucormycosis is insidious and difficult to diagnose. It progresses rapidly and causes high mortality. Rare cases have been reported during ibrutinib use, which have poor prognosis. Through this case, we share the experience of successful diagnosis and treatment. We also emphasize the importance of focusing on high-risk groups, early diagnosis and prompt management. Case description: In this case, a 52-year-old patient was diagnosed with chronic lymphocytic leukemia (CLL) for more than 5 years. He was in remission after rituximab plus fludarabine and cyclophosphamide (RFC) regimen, and relapsed in the fourth year. During the ibrutinib monotherapy, the patient presented with sudden headache. Cranial imaging examination revealed a definite right occipitoparietal lobe mass with extensive edema. A rapid diagnosis of mucormycosis infection was made using metagenomic next-generation sequencing (mNGS). The patient at that time didn't have neutropenia, but he had hypogammaglobulinemia. The infection was treated with amphotericin B cholesteryl sulfate complex, posaconazole, and interventional surgery, and the treatment was successful. At the same time, we considered the control of disease progression in this relapsed patient with, as well as to the drug interaction with posaconazole. We chose the next generation Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib as the treatment, whose safety has been identified. As of the submission date, the patient has been followed up for nearly 1 year, and his disease is stable. Conclusions: When new clinical problems arise in recurrent CLL patients, it is important to identify multiple factors, especially the insidious fungal infections. In particular, the immunocompromised patients should be concerned. CNS mucormycosis is extremely deadly, the early diagnosis will improve the prognosis. In clinical practice, the gold standard diagnosis of mucormycosis is difficult to obtain through pathology. In this case, mNGS was applied to quickly diagnose mucormycosis, enabling earlier treatment and ameliorating the prognosis. Thus, it will help us to early detect this group of people who may be potentially infected. Current guidelines do not recommend the prophylactic use of antifungal agents in treated CLL patients. However, in patients with prior severe infection or hypogammaglobulinemia, intravenous immunoglobulin is recommended to reduce the associated infection rate.
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    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 Medicine
    Background: 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.
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    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 Medicine
    Motivation: 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.
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    Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice.
    (Elsevier, 2015-11-24) Zhao, Zhigang; Chen, Li; Dawlaty, Meelad M.; Pan, Feng; Weeks, Ophelia; Zhou, Yuan; Cao, Zeng; Shi, Hui; Wang, Jiapeng; Lin, Li; Chen, Shi; Yuan, Weiping; Qin, Zhaohui; Ni, Hongyu; Nimer, Stephen D.; Yang, Feng-Chun; Jaenisch, Rudolf; Jin, Peng; Xu, Mingjiang; Department of Pediatrics, IU School of Medicine
    TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2−/− HSC/HPCs showed overlapping and unique 5hmC and 5mC profiles, and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed-onset of myeloid malignancies compared to Tet2−/− mice, and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1/2 individually and together via communication in the pathogenesis of hematological malignancies.
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    Duplicating Complete Dentures with Conventional and Digital Methods: Comparisons of Trueness and Efficiency
    (MDPI, 2022) Chen, Li; Li, Deli; Zhou, Jianfeng; Lin, Wei-Shao; Tan, Jianguo; Prosthodontics, School of Dentistry
    Background: A complete denture (CD) can be duplicated with a conventional or digital protocol. However, there are no comparative studies of these methods. This study aimed to compare the trueness and efficiency of conventional and digital CD duplication methods. Methods: A mandibular CD was digitized as the virtual reference model and duplicated using five methods (n = 10). The trueness (root mean square (RMS)) was calculated for the whole denture and across the dentition, cameo denture extension, and intaglio portions. The manual labor time spent during denture duplication was also recorded at different steps. The trueness and labor time comparisons were statistically analyzed among the five groups (α = 0.05). Results: The conventional group was the least true with the largest RMS (mean, 95% CI) in all of the comparisons. The four digital groups yielded similar trueness values across the dentition, cameo denture extension, and intaglio areas, yet they had a significant difference in the whole denture comparison between the Digital-CBCT-SLA printer (0.17, 0.15-0.19 mm) and Digital-Laboratory Scanner-SLA printer (0.13, 0.11-0.15 mm). The conventional protocol required longer trimming and finishing time (7.55 ± 1.02 min), as well as total labor time (27.64 ± 1.72 min) than the other four digital techniques. Conclusions: The conventional CD duplication method was less true and efficient than digital techniques.
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    Early Wnt Signaling Activation Promotes Inner Ear Differentiation via Cell Caudalization in Mouse Stem Cell-Derived Organoids
    (Oxford University Press, 2023) Tang, Pei-Ciao; Chen, Li; Singh, Sunita; Groves, Andrew K.; Koehler, Karl R.; Liu, Xue Zhong; Nelson, Rick F.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    The inner ear is derived from the otic placode, one of the numerous cranial sensory placodes that emerges from the pre-placodal ectoderm (PPE) along its anterior-posterior axis. However, the molecular dynamics underlying how the PPE is regionalized are poorly resolved. We used stem cell-derived organoids to investigate the effects of Wnt signaling on early PPE differentiation and found that modulating Wnt signaling significantly increased inner ear organoid induction efficiency and reproducibility. Alongside single-cell RNA sequencing, our data reveal that the canonical Wnt signaling pathway leads to PPE regionalization and, more specifically, medium Wnt levels during the early stage induce (1) expansion of the caudal neural plate border (NPB), which serves as a precursor for the posterior PPE, and (2) a caudal microenvironment that is required for otic specification. Our data further demonstrate Wnt-mediated induction of rostral and caudal cells in organoids and more broadly suggest that Wnt signaling is critical for anterior-posterior patterning in the PPE.
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    Editorial: Deciphering Non-Coding Regulatory Variants: Computational and Functional Validation
    (Frontiers, 2021-11) Chen, Li; Li, Mulin Jun; Biostatistics, School of Public Health
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    Enhanced Antibacterial Effect on Zirconia Implant Abutment by Silver Linear-Beam Ion Implantation
    (MDPI, 2023-01-13) Yang, Yang; Liu, Mingyue; Yang, Zhen; Lin, Wei-Shao; Chen, Li; Tan, Jianguo; Prosthodontics, School of Dentistry
    Peri-implant lesions, such as peri-implant mucositis and peri-implantitis, are bacterial-derived diseases that happen around dental implants, compromising the long-term stability and esthetics of implant restoration. Here, we report a surface-modification method on zirconia implant abutment using silver linear-beam ion implantation to reduce the bacterial growth around the implant site, thereby decreasing the prevalence of peri-implant lesions. The surface characteristics of zirconia after ion implantation was evaluated using energy dispersive spectroscopy, X-ray photoelectron spectroscopy, and a contact-angle device. The antibacterial properties of implanted zirconia were evaluated using Streptococcus mutans and Porphyromonas gingivalis. The biocompatibility of the material surface was evaluated using human gingival fibroblasts. Our study shows that the zirconia surface was successfully modified with silver nanoparticles by using the ion-implantation method. The surface modification remained stable, and the silver-ion elution was below 1 ppm after one-month of storage. The modified surface can effectively eliminate bacterial growth, while the normal gingiva’s cell growth is not interfered with. The results of the study demonstrate that a silver-ion-implanted zirconia surface possesses good antibacterial properties and good biocompatibility. The surface modification using silver-ion implantation is a promising method for future usage.
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    Ethnicity-specific and overlapping alterations of brain hydroxymethylome in Alzheimer’s disease
    (Oxford University Press, 2020-01) Qin, Lixia; Xu, Qian; Li, Ziyi; Chen, Li; Li, Yujing; Yang, Nannan; Liu, Zhenhua; Guo, Jifeng; Shen, Lu; Allen, Emily G.; Chen, Chao; Ma, Chao; Wu, Hao; Zhu, Xiongwei; Jin, Peng; Tang, Beisha; Medicine, School of Medicine
    5-Methylcytosine (5mC), generated through the covalent addition of a methyl group to the fifth carbon of cytosine, is the most prevalent DNA modification in humans and functions as a critical player in the regulation of tissue and cell-specific gene expression. 5mC can be oxidized to 5-hydroxymethylcytosine (5hmC) by ten–eleven translocation (TET) enzymes, which is enriched in brain. Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and several studies using the samples collected from Caucasian cohorts have found that epigenetics, particularly cytosine methylation, could play a role in the etiological process of AD. However, little research has been conducted using the samples of other ethnic groups. Here we generated genome-wide profiles of both 5mC and 5hmC in human frontal cortex tissues from late-onset Chinese AD patients and cognitively normal controls. We identified both Chinese-specific and overlapping differentially hydroxymethylated regions (DhMRs) with Caucasian cohorts. Pathway analyses revealed specific pathways enriched among Chinese-specific DhMRs, as well as the shared DhMRs with Caucasian cohorts. Furthermore, two important transcription factor-binding motifs, hypoxia-inducible factor 2α (HIF2α) and hypoxia-inducible factor 1α (HIF1α), were enriched in the DhMRs. Our analyses provide the first genome-wide profiling of DNA hydroxymethylation of the frontal cortex of AD patients from China, emphasizing an important role of 5hmC in AD pathogenesis and highlighting both ethnicity-specific and overlapping changes of brain hydroxymethylome in AD.