Publications by authors named "Jiayu Chen"

230 Publications

Altered sperm tsRNAs in aged male contribute to anxiety-like behavior in offspring.

Aging Cell 2021 Sep 27;20(9):e13466. Epub 2021 Aug 27.

Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.

Parental age at first pregnancy is increasing worldwide. The offspring of aged father has been associated with higher risk of several neuropsychiatric disorders, such as schizophrenia and autism, but the underlying mechanism remains elusive. Here we report that advanced paternal age in mice alters the profile of transfer RNA-derived small RNAs (tsRNAs). Injection of sperm tsRNAs from aged male mice into zygotes induced anxiety-like behaviors in F1 males. RNA sequencing of the cerebral cortex and hippocampus of those F1 male mice altered the gene expression of dopaminergic synapse and neurotrophin. tsRNAs from aged male mice injection also altered the neuropsychiatry-related gene expression in two-cell and blastocyst stage embryos. More importantly, the sperm tsRNA profile changes significantly during aging in human. The up-regulated sperm tsRNA target genes were involved in neurogenesis and nervous system development. These results suggest that aging-related changes of sperm tsRNA may contribute to the intergenerational transmission of behavioral traits.
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http://dx.doi.org/10.1111/acel.13466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441364PMC
September 2021

Correction to: Nuclear m6A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos.

Protein Cell 2021 Aug 25. Epub 2021 Aug 25.

Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, China.

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http://dx.doi.org/10.1007/s13238-021-00853-8DOI Listing
August 2021

ANXA1 as a Prognostic and Immune Microenvironmental Marker for Gliomas Based on Transcriptomic Analysis and Experimental Validation.

Front Cell Dev Biol 2021 4;9:659080. Epub 2021 Aug 4.

Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

The tumor microenvironment (TME) plays an important role in the growth and invasion of glioma. This study aimed to analyze the composition of the immune microenvironment in glioma samples and analyze the important differentially expressed genes to identify novel immune-targeted therapy for glioma. We downloaded transcriptomic data of 669 glioma samples from The Cancer Genome Atlas database. CIBERSORT and ESTIMATE methods were used to calculate the proportion of tumor-infiltrating immune cells and ratio of immune and stromal components in the TME. The differentially expressed genes (DEGs) were screened by comparing the genes expressed by both stromal and immune cells. Annexin A1 (ANXA1) was determined to be an important prognostic indicator through the common overlap of univariate Cox regression analysis and protein-protein interaction network analysis. The proportion of tumor-infiltrating immune cells, calculated by CIBERSORT algorithm, had a significant difference in distribution among the high and low ANXA1 expression groups, indicating that ANXA1 could be an important immune marker of TME. Furthermore, ANXA1 level was positively correlated with the histopathological factors and negatively related to the survival of glioma patients based on the analysis of multiple databases. Finally, experiments verified that antagonizing ANXA1 expression promoted cell apoptosis and inhibited the invasion and migration capacities of glioma cells. Therefore, ANXA1 due to its immune-related functions, can be an important prognostic indicator and immune microenvironmental marker for gliomas. Further studies are warranted to confirm ANXA1 as a potential immunotherapeutic target for gliomas.
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http://dx.doi.org/10.3389/fcell.2021.659080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371204PMC
August 2021

Strain-Driven Polarized Electric Field-Promoted Photocatalytic Activity in Borate-Based CsCdBO Bulk Materials.

ACS Appl Mater Interfaces 2021 Jul 16;13(29):34202-34212. Epub 2021 Jul 16.

School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China.

Piezoelectrically polarized electric field can provide a strong driving force for the separation of the photoinduced charge carriers that has attracted a wide attention in the field of photocatalysis. In this paper, a new type of piezoelectric borate material CsCdBO exhibits a high efficiency for the degradation of typical organic pollutants under the synergistic effects of strain and light conditions. The oxidation rate constant of the synergistic effect is 0.653 min, which is 3.77 times that of just under visible light irradiation. Further, the material shows a higher efficiency when treated both under the clockwise stirring direction and a high stirring speed. A characteristic piezoresponse hysteresis loop was detected using the piezoresponse force microscopy (PFM) approach. The strain-driven polarized electric field facilitates to promote the photoinduced electron-hole pair separation, thus enhancing the photocatalytic activity. The present work provides a new direction of the borate with a noncentrosymmetric structure in the environmental remediation.
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http://dx.doi.org/10.1021/acsami.1c07340DOI Listing
July 2021

Transformation of acellular dermis matrix with dicalcium phosphate into 3D porous scaffold for bone regeneration.

J Biomater Sci Polym Ed 2021 Aug 4:1-17. Epub 2021 Aug 4.

Department of Orthopedics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.

Animal derived biomaterials have attracted much attentions in treating large size bone defect due to their excellent biocompatibility and potent bioactivities offered by the biomacromolecules and growth factors contained in these materials. Dermis-derived matrix (ADM) has been used as skin grafts and wound dressings for decades, however its application in bone tissue engineering has been largely limited as ADM possesses a dense structure which does not support bone tissue ingrowth. Recently, we have successfully fabricated porous scaffold structure using an ADM with the aid of micronization technique. When integrated with inorganic components such as calcium phosphate, ADM could be transformed to bone graft substitutes with desirable osteogenic properties. While purified and chemically cross-linked collagen has lost its natural structure, our ADM successfully preserved natural tropocollagen structure, as well as other bioactive components. A composite scaffold was fabricated by incorporating dicalcium phosphate (DCP) microparticles into ADM microfibers and freeze-dried to form a highly porous structure. Unlike conventional ADM materials, this scaffold possesses high porosity with interconnected pores. More importantly, our evaluation data demonstrated that it performed much more effective in treating critical bone defects in comparison with best commercial product on the market. In a head-to-head comparison with a commercial bone graft material Bongold, the ADM/DCP scaffold showed superior osteogenic capacity by filling the defect with well-organized new bone tissue in a rabbit radius segmental defect model. Put together, our results exhibited a novel bone graft substitute was developed by circumventing processing barriers associated with natural ADM, which offers another novel bone graft substitute for bone regeneration.
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http://dx.doi.org/10.1080/09205063.2021.1955817DOI Listing
August 2021

DNA methylation under the major depression pathway predicts pediatric quality of life four-month post-pediatric mild traumatic brain injury.

Clin Epigenetics 2021 Jul 12;13(1):140. Epub 2021 Jul 12.

Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University, 55 Park Place NE, 18th Floor, Atlanta, GA, 30303, USA.

Background: Major depression has been recognized as the most commonly diagnosed psychiatric complication of mild traumatic brain injury (mTBI). Moreover, major depression is associated with poor outcomes following mTBI; however, the underlying biological mechanisms of this are largely unknown. Recently, genomic and epigenetic factors have been increasingly implicated in the recovery following TBI.

Results: This study leveraged DNA methylation within the major depression pathway, along with demographic and behavior measures (features used in the clinical model) to predict post-concussive symptom burden and quality of life four-month post-injury in a cohort of 110 pediatric mTBI patients and 87 age-matched healthy controls. The results demonstrated that including DNA methylation markers in the major depression pathway improved the prediction accuracy for quality of life but not persistent post-concussive symptom burden. Specifically, the prediction accuracy (i.e., the correlation between the predicted value and observed value) of quality of life was improved from 0.59 (p = 1.20 × 10) (clinical model) to 0.71 (p = 3.89 × 10); the identified cytosine-phosphate-guanine sites were mainly in the open sea regions and the mapped genes were related to TBI in several molecular studies. Moreover, depression symptoms were a strong predictor (with large weights) for both post-concussive symptom burden and pediatric quality of life.

Conclusion: This study emphasized that both molecular and behavioral manifestations of depression symptoms played a prominent role in predicting the recovery process following pediatric mTBI, suggesting the urgent need to further study TBI-caused depression symptoms for better recovery outcome.
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http://dx.doi.org/10.1186/s13148-021-01128-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274037PMC
July 2021

GSTP1 positive prostatic adenocarcinomas are more common in Black than White men in the United States.

PLoS One 2021 30;16(6):e0241934. Epub 2021 Jun 30.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

GSTP1 is a member of the Glutathione-S-transferase (GST) family silenced by CpG island DNA hypermethylation in 90-95% of prostate cancers. However, prostate cancers expressing GSTP1 have not been well characterized. We used immunohistochemistry against GSTP1 to examine 1673 primary prostatic adenocarcinomas on tissue microarrays (TMAs) with redundant sampling from the index tumor from prostatectomies. GSTP1 protein was positive in at least one TMA core in 7.7% of cases and in all TMA cores in 4.4% of cases. The percentage of adenocarcinomas from Black patients who had any GSTP1 positive TMA cores was 14.9%, which was 2.5 times higher than the percentage from White patients (5.9%; P < 0.001). Further, the percentages of tumors from Black patients who had all TMA spots positive for GSTP1 (9.5%) was 3-fold higher than the percentage from White patients (3.2%; P<0.001). In terms of association with other molecular alterations, GSTP1 positivity was enriched in ERG positive cancers among Black men. By in situ hybridization, GSTP1 mRNA expression was concordant with protein staining, supporting the lack of silencing of at least some GSTP1 alleles in GSTP1-positive tumor cells. This is the first report revealing that GSTP1-positive prostate cancers are substantially over-represented among prostate cancers from Black compared to White men. This observation should prompt additional studies to determine whether GSTP1 positive cases represent a distinct molecular subtype of prostate cancer and whether GSTP1 expression could provide a biological underpinning for the observed disparate outcomes for Black men.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241934PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244883PMC
June 2021

Monocarboxylate Transporter 4 Triggered Cell Pyroptosis to Aggravate Intestinal Inflammation in Inflammatory Bowel Disease.

Front Immunol 2021 19;12:644862. Epub 2021 May 19.

Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

NLRP3 inflammasome has emerged as a crucial regulator of inflammatory bowel disease (IBD) characterized by a chronic inflammatory disease of the gastrointestinal tract. The expression of MCT4 is significantly increased in intestinal mucosal tissue of IBD, which has been identified to regulate intestinal barrier function. However, the function of MCT4 in cell pyroptosis remained unknown. In this study, we have established a stable cell line with MCT4 overexpression in HT-29 and CaCO2 cells, respectively. Functional analysis revealed that ectopic expression of MCT4 in CaCO2 cells contributed to cell pyroptosis as evidenced by LDH assay, which is largely attributed to Caspase-1-mediated canonical pyroptosis, but not Caspase-4 and Caspase-5, leading to cleave pro-IL-1β and IL-18 into mature form and release mediated by cleaved GSDMD. Mechanically, MCT4 overexpression in HT-29 and CaCO2 cell triggered the phosphorylation of ERK1/2 and NF-B p65, while inhibition of MCT4 by MCT inhibitor -Cyano-4-hydroxycinnamic acid (-CHCA) in HT-29 and CaCO2 cells led to a significant downregulation of ERK1/2 and NF-B activity. What's more, blockade of ERK1/2-NF-B pathway could reverse the promotion effect of MCT4 on IL-1β expression. Importantly, both MCT4 and Caspase-1, GSDMD were significantly increased in patients with IBD, and a positive clinical correlation between MCT4 and Caspase-1 expression was observed (p < 0.001). Taken together, these findings suggested that MCT4 promoted Caspase-1-mediated canonical cell pyroptosis to aggravate intestinal inflammation in intestinal epithelial cells (IECs) through the ERK1/2-NF-B pathway.
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http://dx.doi.org/10.3389/fimmu.2021.644862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170300PMC
May 2021

Involved in Innate Immunity by Activating Tyrosinase-Mediated Melanin Synthesis in .

Front Immunol 2021 20;12:626493. Epub 2021 May 20.

Fishery College, Guangdong Ocean University, Zhanjiang, China.

The microphthalmia-associated transcription factor (MITF) is an important transcription factor that plays a key role in melanogenesis, cell proliferation, survival and immune defense in vertebrate. However, its function and function mechanism in bivalve are still rarely known. In this research, first, a gene was characterized from (). The contained an open reading frame of 1,350 bp, encoding a peptide of 449 deduced amino acids with a highly conserved basic helix-loop-helix-leucine zipper (bHLH-LZ) domain. The PpMITF shared 55.7% identity with amino acid sequence of (). Tissue distribution analysis revealed that was highly expressed in mantle and hemocytes, which were important tissues for color formation and innate immunity. Second, the functions of in melanin synthesis and innate immunity were identified. The silencing significantly decreased the tyrosinase activity and melanin content, indicating involved in melanin synthesis of Meanwhile, the silencing clearly down-regulated the expression of (B cell lymphoma/leukemia-2 gene) and antibacterial activity of hemolymph supernatant, indicating that involved in innate immunity of Third, the function mechanism of in immunity was analyzed. The promoter sequence analysis of tyrosinase () revealed two highly conserved E-box elements, which were specifically recognized by HLH-LZ of MITF. The luciferase activities analysis showed that could activate the E-box in promoter through highly conserved bHLH-LZ domain, and demonstrated that involved in melanin synthesis and innate immunity by regulating tyrosinase expression. Finally, melanin from , the final production of --melanin pathway, was confirmed to have direct antibacterial activity. The results collectively demonstrated that played a key role in innate immunity through activating tyrosinase-mediated melanin synthesis in
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http://dx.doi.org/10.3389/fimmu.2021.626493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173187PMC
September 2021

Carbon nanoparticles combined with indocyanine green for sentinel lymph node detection in endometrial carcinoma.

J Surg Oncol 2021 Sep 4;124(3):411-419. Epub 2021 Jun 4.

Department of Obstetrics & Gynecology, Peking University People's Hospital, Beijing, China.

Objective: To evaluate the feasibility and clinical value of the combination of carbon nanoparticles (CNPs) and indocyanine green (ICG) for identifying sentinel lymph nodes (SLNs) in endometrial cancer.

Materials And Methods: About 153 patients with endometrial cancer were recruited from July 2015 to May 2019. All patients underwent SLN biopsy according to the SLN algorithm for surgical staging with ICG and/or CNPs. The detection rate, factors associated with the detection rate, sensitivity, and negative predictive value (NPV) of SLNs were analyzed.

Results: The detection rates of SLNs with the combined method were the highest among the different methods. As calculated per hemipelvis, the sensitivity and NPV with ICG alone or with ICG plus CNPs were 100%. With CNP, tumor Grade 3 and laparoscopy were related to unsuccessful overall SLN mapping while tumor diameter greater than 2 cm and laparoscopy were statistically associated with failed bilateral mapping. With ICG, a higher body mass index was significantly associated with unsuccessful bilateral detection of SLN.

Conclusion: SLN assessment in endometrial cancer is feasible and safe with high sensitivity and high NPV when ICG and CNPs are combined and in low-risk patients. It is a superior option to use CNPs in laparotomy for patients with endometrial cancer.
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http://dx.doi.org/10.1002/jso.26518DOI Listing
September 2021

Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection.

EMBO Rep 2021 07 13;22(7):e51678. Epub 2021 May 13.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.
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http://dx.doi.org/10.15252/embr.202051678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256295PMC
July 2021

Targeted and nontargeted metabolomics analysis for determining the effect of storage time on the metabolites and taste quality of keemun black tea.

Food Chem 2021 Oct 24;359:129950. Epub 2021 Apr 24.

State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei 230036, China; International Joint Laboratory on Tea Chemistry and Health Effects of Ministry of Education, Anhui Agricultural University, Hefei 230036, China. Electronic address:

The black tea could be stored for a long time, and subsequently affects the flavor characteristics. In the present study, the effects of storage years (1, 2, 3, 4, 5, 10, 17 and 20 years) on the chemical profiling and taste quality of keemun black tea (KBT) were compared by metabolomics and quantitative sensory evaluation. The main polyphenols were degraded during the storing, especially 10-year storage, but caffeine and theobromine were stable. The intensity of bitterness, astringency, umami was negatively correlated to storage years, with correlation coefficient at -0.95, -0.91 and -0.83 respectively, whereas sweetness had positive correlation coefficient at 0.74. Quinic acid, galloylated catechins, linolenic acid, linoleic acid, malic acid, palamitic acid, and theaflavin-3́-gallate were marker compounds which were responsible for distinguishing short and long time preserved KBT. The contents of fatty acids were positively correlated to storage time and sweet intensity.
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http://dx.doi.org/10.1016/j.foodchem.2021.129950DOI Listing
October 2021

Nuclear mA reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos.

Protein Cell 2021 Jun 22;12(6):455-474. Epub 2021 Apr 22.

Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, China.

N-methyladenosine (mA) on chromosome-associated regulatory RNAs (carRNAs), including repeat RNAs, plays important roles in tuning the chromatin state and transcription, but the intrinsic mechanism remains unclear. Here, we report that YTHDC1 plays indispensable roles in the self-renewal and differentiation potency of mouse embryonic stem cells (ESCs), which highly depends on the mA-binding ability. Ythdc1 is required for sufficient rRNA synthesis and repression of the 2-cell (2C) transcriptional program in ESCs, which recapitulates the transcriptome regulation by the LINE1 scaffold. Detailed analyses revealed that YTHDC1 recognizes mA on LINE1 RNAs in the nucleus and regulates the formation of the LINE1-NCL partnership and the chromatin recruitment of KAP1. Moreover, the establishment of H3K9me3 on 2C-related retrotransposons is interrupted in Ythdc1-depleted ESCs and inner cell mass (ICM) cells, which consequently increases the transcriptional activities. Our study reveals a role of mA in regulating the RNA scaffold, providing a new model for the RNA-chromatin cross-talk.
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http://dx.doi.org/10.1007/s13238-021-00837-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160034PMC
June 2021

Reward Processing in Novelty Seekers: A Transdiagnostic Psychiatric Imaging Biomarker.

Biol Psychiatry 2021 Jan 30. Epub 2021 Jan 30.

Centre for Population Neuroscience and Stratified Medicine, Institute for Science and Technology of Brain-Inspired Intelligence, Fudan University, Shanghai, China; Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.

Background: Dysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues.

Methods: A subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS-associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels.

Results: Multimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%.

Conclusions: Adolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS-associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.
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http://dx.doi.org/10.1016/j.biopsych.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322149PMC
January 2021

C3AR1 mRNA as a Potential Therapeutic Target Associates With Clinical Outcomes and Tumor Microenvironment in Osteosarcoma.

Front Med (Lausanne) 2021 5;8:642615. Epub 2021 Mar 5.

Department of Orthopedic Surgery, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.

Targeting cancer-specific messenger RNAs (mRNAs) may offer novel insights into therapeutic strategies in osteosarcoma. This study aimed to discover possible osteosarcoma-specific mRNA and probe its biological functions. Based on mRNA-seq data from the TARGET database, stromal and immune scores were estimated for each osteosarcoma sample via the ESTIMATE algorithm. Stromal and immune mRNAs were obtained via integration of differentially expressed mRNAs between high and low stromal / immune score groups. Among hub and prognostic mRNAs, C3AR1 mRNA was focused and its prognostic value was assessed. The associations between C3AR1 mRNA and immune cells were analyzed via the CIBERSORT algorithm. Its expression was verified in osteosarcoma tissues and cells by RT-qPCR and western blot. The functions of C3AR1 were investigated by a series of experiments. Low stromal and immune scores were both indicative of unfavorable outcomes for osteosarcoma patients. Eighty-eight up-regulated and seven down-regulated stromal and immune mRNAs were identified. Among 30 hub mRNAs, low expression of C3AR1 mRNA indicated worse outcomes than its high expression. There was a lower mRNA expression of C3AR1 in metastatic than non-metastatic osteosarcoma. C3AR1 mRNA was closely correlated to various immune cells such as macrophages. C3AR1 was verified to be down-regulated in osteosarcoma tissues and cells. Its overexpression suppressed proliferation, migration and invasion and induced apoptosis in osteosarcoma cells. C3AR1 mRNA could be a promising therapeutic target for osteosarcoma, linked with prognosis and tumor microenvironment.
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http://dx.doi.org/10.3389/fmed.2021.642615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973027PMC
March 2021

Rabeprazole suppresses cell proliferation in gastric epithelial cells by targeting STAT3-mediated glycolysis.

Biochem Pharmacol 2021 06 17;188:114525. Epub 2021 Mar 17.

Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China. Electronic address:

The dysregulation of glycolysis leads to serials of disease. Rabeprazole is a representative of proton pump inhibitors and widely used in anti-ulcer treatment. However, the function of Rabeprazole on glycolysis in gastric epithelial cells remained to be identified. In this study, 30(Helicobacter pylori)H. pylori-negative cases and 26H. pylori-positive cases treated with Rabeprazole were recruited. The qPCR and Western blotting results showed that Rabeprazole suppressed cell proliferation by inhibition of HK2-mediated glycolysis in BGC823 cells, leading to decrease glucose uptake and lactate production in a dose-dependent way. Furthermore, the phosphorylation of signal transducer and activator of transcription 3 (STAT3) was drastically reduced in response to Rabeprazole stimulation, leading to attenuate STAT3 nuclear translocation. Luciferase and Chromatin immunoprecipitation (ChIP) analysis showed that Rabeprazole treatment led to a significant inhibition of the binding of STAT3 to the promoter of the HK2 gene, repressing transcriptional activation of HK2. Moreover, the ectopic expression of STAT3 in BGC823 cells resulted in recovery of HK2 transactivation and cell proliferation in Rabeprazole-treated cells. Most importantly, HK2 expression was significantly increased in H. pylori-infected gastric mucosa. These findings suggested that Rabeprazole inhibited cell proliferation by targeting STAT3/HK2 signaling-mediated glucose metabolism in gastric epithelial cells. Therefore, targeting HK2 is an alternative strategy in improving the treatment of patients with H. pylori infection.
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http://dx.doi.org/10.1016/j.bcp.2021.114525DOI Listing
June 2021

High Expression of LINC01268 is Positively Associated with Hepatocellular Carcinoma Progression via Regulating MAP3K7.

Onco Targets Ther 2021 8;14:1753-1769. Epub 2021 Mar 8.

Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, 110001, People's Republic of China.

Objective: As one of the most common neoplastic diseases, hepatocellular carcinoma (HCC) has a high morbidity and mortality, which seriously threatens human health and places a heavy burden on society and medical care. At present, effective early diagnosis, prognosis and treatment of HCC are limited. Altered gene expression patterns of lncRNA are associated with the occurrence, development and prognosis of various malignancies, including HCC. The aim of this study was to investigate the correlation between the expression of LINC01268 and HCC, and to elucidate the potential underlying molecular mechanism.

Methods: Expression level and localization of LINC01268 in human liver cancer cells and HCC tissues were investigated using RT-qPCR and fluorescent in situ hybridization (FISH), respectively. Correlation of expression levels of LINC01268 and MAP3K7 with differentiation and poor overall patient survival of HCC were analyzed using in house collected and publicly available HCC tissue data. RT-qPCR and Western blot were applied to inspect the effects of depletion and overexpression of LINC01268 on MAP3K7 expression. HCC cell proliferation and apoptosis were also investigated by simultaneous overexpression of LINC01268 and knockdown of MAP3K7, in order to delineate that MAP3K7 is a downstream effector of LINC01268.

Results: In this study, we identified that LINC01268 was highly expressed in HCC cell lines and tissues. High LINC01268 expression level was associated with lower HCC nodule number, moderate/poor differentiation and poor overall survival. Knockdown of LINC01268 inhibited the proliferation of HCC cells, which was enhanced by overexpression of LINC01268. Co-expression analysis implied an interaction between LINC01268 and MAP3K7. Similar to LINC01268, MAP3K7 was highly expressed in HCC cells, and positively correlated with moderate/poor differentiation as well as poor prognosis. Knockdown of LINC01268 in HCC cell lines led to reduction of MAP3K7 at both mRNA and protein levels. Phenotypic effects due to LINC01268 overexpression in HCC cells were reversed by knockdown of MAP3K7.

Conclusion: Taken together, the abnormal high expression of LINC01268 is associated with HCC progression via regulating MAP3K7, suggesting LINC01268 as a novel marker for HCC prognosis and potentially a new therapeutic target.
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http://dx.doi.org/10.2147/OTT.S295814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954037PMC
March 2021

Sparse deep neural networks on imaging genetics for schizophrenia case-control classification.

Hum Brain Mapp 2021 Jun 16;42(8):2556-2568. Epub 2021 Mar 16.

Department of Computer Science, Georgia State University, Atlanta, Georgia, USA.

Deep learning methods hold strong promise for identifying biomarkers for clinical application. However, current approaches for psychiatric classification or prediction do not allow direct interpretation of original features. In the present study, we introduce a sparse deep neural network (DNN) approach to identify sparse and interpretable features for schizophrenia (SZ) case-control classification. An L -norm regularization is implemented on the input layer of the network for sparse feature selection, which can later be interpreted based on importance weights. We applied the proposed approach on a large multi-study cohort with gray matter volume (GMV) and single nucleotide polymorphism (SNP) data for SZ classification. A total of 634 individuals served as training samples, and the classification model was evaluated for generalizability on three independent datasets of different scanning protocols (N = 394, 255, and 160, respectively). We examined the classification power of pure GMV features, as well as combined GMV and SNP features. Empirical experiments demonstrated that sparse DNN slightly outperformed independent component analysis + support vector machine (ICA + SVM) framework, and more effectively fused GMV and SNP features for SZ discrimination, with an average error rate of 28.98% on external data. The importance weights suggested that the DNN model prioritized to select frontal and superior temporal gyrus for SZ classification with high sparsity, with parietal regions further included with lower sparsity, echoing previous literature. The results validate the application of the proposed approach to SZ classification, and promise extended utility on other data modalities and traits which ultimately may result in clinically useful tools.
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http://dx.doi.org/10.1002/hbm.25387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090768PMC
June 2021

RNA helicase DDX5 acts as a critical regulator for survival of neonatal mouse gonocytes.

Cell Prolif 2021 May 5;54(5):e13000. Epub 2021 Mar 5.

CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.

Objectives: Mammalian spermatogenesis is a biological process of male gamete formation. Gonocytes are the only precursors of spermatogonial stem cells (SSCs) which develop into mature spermatozoa. DDX5 is one of DEAD-box RNA helicases and expresses in male germ cells, suggesting that Ddx5 plays important functions during spermatogenesis. Here, we explore the functions of Ddx5 in regulating the specification of gonocytes.

Materials And Methods: Germ cell-specific Ddx5 knockout (Ddx5 ) mice were generated. The morphology of testes and epididymides and fertility in both wild-type and Ddx5 mice were analysed. Single-cell RNA sequencing (scRNA-seq) was used to profile the transcriptome in testes from wild-type and Ddx5 mice at postnatal day (P) 2. Dysregulated genes were validated by single-cell qRT-PCR and immunofluorescent staining.

Results: In male mice, Ddx5 was expressed in germ cells at different stages of development. Germ cell-specific Ddx5 knockout adult male mice were sterile due to completely devoid of germ cells. Male germ cells gradually disappeared in Ddx5 mice from E18.5 to P6. Single-cell transcriptome analysis showed that genes involved in cell cycle and glial cell line-derived neurotrophic factor (GDNF) pathway were significantly decreased in Ddx5-deficient gonocytes. Notably, Ddx5 ablation impeded the proliferation of gonocytes.

Conclusions: Our study reveals the critical roles of Ddx5 in fate determination of gonocytes, offering a novel insight into the pathogenesis of male sterility.
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http://dx.doi.org/10.1111/cpr.13000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088469PMC
May 2021

SIRT1 and gynecological malignancies (Review).

Oncol Rep 2021 04 2;45(4). Epub 2021 Mar 2.

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.

Sirtuin 1 (SIRT1), a member of the sirtuin protein family, is a nicotinamide adenine dinucleotide (NAD)‑dependent type III histone deacetylase and mono‑ADP‑ribosyltransferase. SIRT1 can deacetylate histones (H1, H3, and H4) and non‑histone proteins, and it is widely involved in various physiological and pathological processes in the body, including metabolism, aging, transcription, DNA damage and repair, apoptosis, cell cycle regulation, inflammation and cancer. Research has shown that SIRT1 is involved in tumorigenesis, tumor metastasis and chemotherapy resistance, but it exerts opposing effects and plays different roles in different pathogenic processes. Recent studies have demonstrated that SIRT1 may be implicated in the pathogenesis, development, treatment and prognosis of tumors; however, its role in gynecological tumors remains elusive. The aim of the present review was to summarize the pathogenic roles of SIRT1 in cancer, and to provide what is, to the best of our knowledge, the first review of recent advances involving SIRT1 in cervical cancer, endometrial cancer (EC) and ovarian cancer (OC). In addition, the critical research gaps regarding SIRT1, particularly its potential involvement in the concurrence of EC and cervical cancer and its antagonistic effect against poly(ADP‑ribose) polymerase inhibitors in OC, were highlighted.
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http://dx.doi.org/10.3892/or.2021.7994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934219PMC
April 2021

Unique Patterns of H3K4me3 and H3K27me3 in 2-Cell-like Embryonic Stem Cells.

Stem Cell Reports 2021 03 25;16(3):458-469. Epub 2021 Feb 25.

Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address:

A small subgroup of embryonic stem cells (ESCs) exhibit molecular features similar to those of two-cell embryos (2C). However, it remains elusive whether 2C-like cells and 2C embryos share similar epigenetic features. Here, we map the genome-wide profiles of histone H3K4me3 and H3K27me3 in 2C-like cells. We found that the majority of genes in 2C-like cells inherit their histone status from ESCs. Among the genes showing a switch in their histone methylation status during 2C-like transitions, only a small number acquire 2C-embryo epigenetic signatures. In contrast, broad H3K4me3 domains display extensive loss in 2C-like cells. Most of the differentially expressed genes display decreased H3K4me3 and H3K27me3 levels in 2C-like cells, whereas de novo H3K4me3 deposition is closely linked with the expression levels of upregulated 2C-specific genes. Taken together, our study reveals the unique epigenetic profiles of 2C-like cells, facilitating the further exploration of totipotency in the future.
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http://dx.doi.org/10.1016/j.stemcr.2021.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940259PMC
March 2021

Coupling urban 3-D information and circuit theory to advance the development of urban ecological networks.

Conserv Biol 2021 Aug 21;35(4):1140-1150. Epub 2021 Jan 21.

Jiangsu Provincial Key Laboratory of Geographic Information Science & Technology,School of Geography and Ocean Science, Nanjing University, Xianlin Avenue 163, Nanjing, 210023, China.

Ongoing, rapid urban growth accompanied by habitat fragmentation and loss challenges biodiversity conservation and leads to decreases in ecosystem services. Application of the concept of ecological networks in the preservation and restoration of connections among isolated patches of natural areas is a powerful conservation strategy. However, previous approaches often failed to objectively consider the impacts of complex 3-D city environments on ecological niches. We used airborne lidar-derived information on the 3-D structure of the built environment and vegetation and detailed land use and cover data to characterize habitat quality, niche diversity, and human disturbance and to predict habitat connectivity among 38 identified habitat core areas (HCAs) in Nanjing, China. We used circuit theory and Linkage Mapper to create a landscape resistance layer, simulate habitat connectivity, and identify and prioritize important corridors. We mapped 64 links by using current flow centrality to evaluate each HCA's contribution and the links that facilitate intact connectivity. Values were highest for HCA links located in the west, south, and northeast of the study area, where natural forests with complex 3-D structures predominate. Two smaller HCA areas had high centrality scores relative to their extents, which means they could act as important stepping stones in connectivity planning. The mapped pinch-point regions had narrow and fragile links among the HCAs, suggesting they require special protection. The barriers with the highest impact scores were mainly located at the HCA connections to Purple Mountain and, based on these high scores, are more likely to indicate important locations that can be restored to improve potential connections. Our novel framework allowed us to sufficiently convey spatially explicit information to identify targets for habitat restoration and potential pathways for species movement and dispersal. Such information is critical for assessing existing or potential habitats and corridors and developing strategic plans to balance habitat conservation and other land uses based on scientifically informed connectivity planning and implementation.
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http://dx.doi.org/10.1111/cobi.13682DOI Listing
August 2021

Transplanting -silenced bone marrow mesenchymal stem cells promote neurological function recovery in TBI mice.

Aging (Albany NY) 2020 12 19;13(2):2822-2850. Epub 2020 Dec 19.

Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Bone marrow mesenchymal stem cells (BMMSCs)-based therapy has emerged as a promising novel therapy for Traumatic Brain Injury (TBI). However, the therapeutic quantity of viable implanted BMMSCs necessary to initiate efficacy is still undetermined. Increased oxidative stress following TBI, which leads to the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase signaling pathway, has been implicated in accounting for the diminished graft survival and therapeutic effect. To prove this assertion, we silenced the expression of NADPH subunits (p22-phox, p47-phox, and p67-phox) and small GTPase Rac1 in BMMSCs using shRNA. Our results showed that silencing these proteins significantly reduced oxidative stress and cell death/apoptosis, and promoted implanted BMMSCs proliferation after TBI. The most significant result was however seen with silencing, which demonstrated decreased expression of apoptotic proteins, enhanced survival ratio, reduction in TBI lesional volume and significant improvement in neurological function post shRac1-BMMSCs transplantation. Additionally, two RNA-seq hub genes ( and ) were identified to play critical roles in shRac1-mediated cell survival. In summary, we propose that knockdown of gene could significantly boost cell survival and promote the recovery of neurological functions after BMMSCs transplantation in TBI mice.
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http://dx.doi.org/10.18632/aging.202334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880331PMC
December 2020

Dcaf11 activates Zscan4-mediated alternative telomere lengthening in early embryos and embryonic stem cells.

Cell Stem Cell 2021 04 23;28(4):732-747.e9. Epub 2020 Dec 23.

Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Qingdao 266071, China. Electronic address:

Telomeres play vital roles in ensuring chromosome stability and are thus closely linked with the onset of aging and human disease. Telomeres undergo extensive lengthening during early embryogenesis. However, the detailed molecular mechanism of telomere resetting in early embryos remains unknown. Here, we show that Dcaf11 (Ddb1- and Cul4-associated factor 11) participates in telomere elongation in early embryos and 2-cell-like embryonic stem cells (ESCs). The deletion of Dcaf11 in embryos and ESCs leads to reduced telomere sister-chromatid exchange (T-SCE) and impairs telomere lengthening. Importantly, Dcaf11-deficient mice exhibit gradual telomere erosion with successive generations, and hematopoietic stem cell (HSC) activity is also greatly compromised. Mechanistically, Dcaf11 targets Kap1 (KRAB-associated protein 1) for ubiquitination-mediated degradation, leading to the activation of Zscan4 downstream enhancer and the removal of heterochromatic H3K9me3 at telomere/subtelomere regions. Our study therefore demonstrates that Dcaf11 plays important roles in telomere elongation in early embryos and ESCs through activating Zscan4.
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http://dx.doi.org/10.1016/j.stem.2020.11.018DOI Listing
April 2021

Buffer wards for the control of COVID-19 transmission in hospitals.

Clin Transl Med 2020 Nov;10(7):e223

Department of Clinical Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

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http://dx.doi.org/10.1002/ctm2.223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648967PMC
November 2020

Utility of Air Bladder-Derived Nanostructured ECM for Tissue Regeneration.

Front Bioeng Biotechnol 2020 15;8:553529. Epub 2020 Oct 15.

Department of Orthopedics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China.

Exploration for ideal bone regeneration materials still remains a hot research topic due to the unmet clinical challenge of large bone defect healing. Bone grafting materials have gradually evolved from single component to multiple-component composite, but their functions during bone healing still only regulate one or two biological processes. Therefore, there is an urgent need to develop novel materials with more complex composition, which convey multiple biological functions during bone regeneration. Here, we report an naturally nanostructured ECM based composite scaffold derived from fish air bladder and combined with dicalcium phosphate (DCP) microparticles to form a new type of bone grafting material. The DCP/acellular tissue matrix (DCP/ATM) scaffold demonstrated porous structure with porosity over 65% and great capability of absorbing water and other biologics. cell culture study showed that DCP/ATM scaffold could better support osteoblast proliferation and differentiation in comparison with DCP/ADC made from acid extracted fish collagen. Moreover, DCP/ATM also demonstrated more potent bone regenerative properties in a rat calvarial defect model, indicating incorporation of ECM based matrix in the scaffolds could better support bone formation. Taken together, this study demonstrates a new avenue toward the development of new type of bone regeneration biomaterial utilizing ECM as its key components.
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http://dx.doi.org/10.3389/fbioe.2020.553529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594528PMC
October 2020

Effects of Herba Erigerontis injection on pharmacodynamics and pharmacokinetics of warfarin in rats in vivo.

Basic Clin Pharmacol Toxicol 2021 Mar 20;128(3):386-393. Epub 2020 Nov 20.

Department of Pharmacy, The Second Affiliated Hospital, Harbin Medical University, The Heilongjiang Key Laboratory of Drug Research, Harbin, P.R. China.

Herba Erigerontis injection (HEI) is an aqueous solution derived from whole plants of Erigeron breviscapus, which may be co-administered with warfarin to treat cardiovascular and cerebrovascular disorders. This research was conducted to make sure whether HEI would affect anticoagulation of warfarin to guarantee reasonable medication. The pharmacodynamic study was designed to measure prothrombin time (PT) and activated partial thromboplastin time (APTT) values, and international normalized ratio (INR) values were calculated. For pharmacokinetic study, ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) technology was applied to measure plasma concentrations of warfarin enantiomers. The influence of HEI on plasma protein binding rate of warfarin was assessed by ultrafiltration. Pharmacodynamic study demonstrated that both HEI alone and co-administered with warfarin could increase PT and INR values significantly (P < .01), whereas the APTT values were unaffected (P > .05). Pharmacokinetic study manifested that C , AUC and t prolonged significantly (P < .01) for R/S-warfarin in presence of HEI. Low (3.6 mL/kg), medium (7.2 mL/kg) and high (10.8 mL/kg) doses of HEI could decrease plasma protein binding rate of warfarin significantly (P < .01). The results mean that HEI can potentiate the anticoagulant response of warfarin through both pharmacodynamics and pharmacokinetics.
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http://dx.doi.org/10.1111/bcpt.13531DOI Listing
March 2021

The SIRT6 activator MDL-800 improves genomic stability and pluripotency of old murine-derived iPS cells.

Aging Cell 2020 08 21;19(8):e13185. Epub 2020 Jul 21.

Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.

Cellular reprogramming is an emerging strategy for delaying the aging processes. However, a number of challenges, including the impaired genome integrity and decreased pluripotency of induced pluripotent stem cells (iPSCs) derived from old donors, may hinder their potential clinical applications. The longevity gene, Sirtuin 6 (SIRT6), functions in multiple biological processes such as the maintenance of genome integrity and the regulation of somatic cell reprogramming. Here, for the first time, we demonstrate that MDL-800, a recently developed selective SIRT6 activator, improved genomic stability by activating two DNA repair pathways-nonhomologous end joining (NHEJ) and base excision repair (BER) in old murine-derived iPSCs. More interestingly, we found that pretreating old murine iPSCs, which normally exhibit a restricted differentiation potential, with MDL-800 promoted the formation of teratomas comprised of all three germ layers and robustly stimulated chimera generation. Our findings suggest that pharmacological activation of SIRT6 holds great promise in treating aging-associated diseases with iPSC-based cell therapy.
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http://dx.doi.org/10.1111/acel.13185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431819PMC
August 2020

Network modules linking expression and methylation in prefrontal cortex of schizophrenia.

Epigenetics 2021 Aug 20;16(8):876-893. Epub 2020 Oct 20.

Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USA.

Tremendous work has demonstrated the critical roles of genetics, epigenetics as well as their interplay in brain transcriptional regulations in the pathology of schizophrenia (SZ). There is great success currently in the dissection of the genetic components underlying risk-conferring transcriptomic networks. However, the study of regulating effect of epigenetics in the etiopathogenesis of SZ still faces many challenges. In this work, we investigated DNA methylation and gene expression from the dorsolateral prefrontal cortex (DLPFC) region of schizophrenia patients and healthy controls using weighted correlation network approach. We identified and replicated two expression and two methylation modules significantly associated with SZ. Among them, one pair of expression and methylation modules were significantly overlapped in the module genes which were significantly enriched in astrocyte-associated functional pathways, and specifically expressed in astrocytes. Another two linked expression-methylation module pairs were involved ageing process with module genes mostly related to oligodendrocyte development and myelination, and specifically expressed in oligodendrocytes. Further examination of underlying quantitative trait loci (QTLs) showed significant enrichment in genetic risk of most psychiatric disorders for expression QTLs but not for methylation QTLs. These results support the coherence between methylation and gene expression at the network level, and suggest a combinatorial effect of genetics and epigenetics in regulating gene expression networks specific to glia cells in relation to SZ and ageing process.
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http://dx.doi.org/10.1080/15592294.2020.1827718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331039PMC
August 2021

Dux-Mediated Corrections of Aberrant H3K9ac during 2-Cell Genome Activation Optimize Efficiency of Somatic Cell Nuclear Transfer.

Cell Stem Cell 2021 01 12;28(1):150-163.e5. Epub 2020 Oct 12.

Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Tongji University, Shanghai 200065, China. Electronic address:

Differentiated somatic cells can be reprogrammed to totipotent embryos through somatic cell nuclear transfer (SCNT) with low efficiency. The histone deacetylase inhibitor trichostatin A (TSA) has been found to improve SCNT efficiency, but the underlying mechanism remains undetermined. Here, we examined genome-wide H3K9ac during SCNT embryo development and found that aberrant H3K9ac regions resulted in reduced 2-cell genome activation. TSA treatment largely corrects aberrant acetylation in SCNT embryos with an efficiency that is dictated by the native epigenetic environment. We further identified that the overexpression of Dux greatly improves SCNT efficiency by correcting the aberrant H3K9ac signal at its target sites, ensuring appropriate 2-cell genome activation. Intriguingly, the improvement in development mediated by TSA and Kdm4b is impeded by Dux knockout in SCNT embryos. Together, our study reveals that reprogramming of H3K9ac is important for optimal SCNT efficiency and identifies Dux as a crucial transcription factor in this process.
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http://dx.doi.org/10.1016/j.stem.2020.09.006DOI Listing
January 2021
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