Publications by authors named "Pengyuan Liu"

135 Publications

Black raspberries attenuate colonic adenoma development in mice: Relationship to hypomethylation of promoters and gene bodies.

Food Front 2020 Sep 9;1(3):234-242. Epub 2020 Sep 9.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Recent studies have suggested that in addition to promoter region, DNA methylation in intragenic and intergenic regions also changes during physiological processes and disease. The current study showed that feeding of black raspberries (BRBs) to mice suppressed colon and intestinal tumors. MBDCap-seq suggested that dietary BRBs hypomethylated promoter, intragenic, and intergenic regions. Annotation of those regions highlighted genes in pathways involved in immune regulation, inflammatory signaling, production of nitric oxide and reactive oxygen species, and progression of colorectal cancer. BRB phytochemicals (e.g., ellagic acid, anthocyanins, oligosaccharides) and their gut bacterial metabolites (e.g., urolithin, protocatechuic acid, short-chain fatty acids) inhibited DNMT1 and DNMT3B activities in a cell-free assay. Our results suggest that BRBs' hypomethylating activities result from the combined effects of multiple BRB phytochemicals and their gut bacterial metabolites. Because similar substances are found in many plant products, our results with BRBs might also apply to commonly consumed fruits and vegetables.
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http://dx.doi.org/10.1002/fft2.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457619PMC
September 2020

Multi-omics mapping of human papillomavirus integration sites illuminates novel cervical cancer target genes.

Br J Cancer 2021 Sep 15. Epub 2021 Sep 15.

Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.

Background: Integration of human papillomavirus (HPV) into the host genome is a dominant feature of invasive cervical cancer (ICC), yet the tumorigenicity of cis genomic changes at integration sites remains largely understudied.

Methods: Combining multi-omics data from The Cancer Genome Atlas with patient-matched long-read sequencing of HPV integration sites, we developed a strategy for using HPV integration events to identify and prioritise novel candidate ICC target genes (integration-detected genes (IDGs)). Four IDGs were then chosen for in vitro functional studies employing small interfering RNA-mediated knockdown in cell migration, proliferation and colony formation assays.

Results: PacBio data revealed 267 unique human-HPV breakpoints comprising 87 total integration events in eight tumours. Candidate IDGs were filtered based on the following criteria: (1) proximity to integration site, (2) clonal representation of integration event, (3) tumour-specific expression (Z-score) and (4) association with ICC survival. Four candidates prioritised based on their unknown function in ICC (BNC1, RSBN1, USP36 and TAOK3) exhibited oncogenic properties in cervical cancer cell lines. Further, annotation of integration events provided clues regarding potential mechanisms underlying altered IDG expression in both integrated and non-integrated ICC tumours.

Conclusions: HPV integration events can guide the identification of novel IDGs for further study in cervical carcinogenesis and as putative therapeutic targets.
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http://dx.doi.org/10.1038/s41416-021-01545-0DOI Listing
September 2021

Molecular Changes in miRNA in Irradiated Rat Kidneys: Role of miR-34a and its Vascular Targets in the Notch Pathway.

Radiat Res 2021 Jul 30. Epub 2021 Jul 30.

Department of Radiation Oncology, Medical College of Wisconsin, Wauwatosa, Wisconsin.

The mechanism(s) of vascular regression in adult organs remains an unexplored gap. Irradiation to the kidney results in vascular regression and renal failure. The goal of this work was to determine molecular mechanism(s) of radiation-induced vascular regression and its mitigation by the drug lisinopril. Female WAG/RijCmcr rats received either 13 Gy X-ray irradiation, sparing one leg, or no irradiation, the latter serving as age-matched controls. Some irradiated animals received lisinopril. Kidney miRNA-seq was performed 35 days postirradiation, before symptoms of nephropathy. MicroRNA expression profiles were compared with data from humans. MicroRNA targets were predicted using TargetScan and confirmed by qRT-PCR and Western blot. Renal vascular endothelial cell density was evaluated at 100 days to confirm vascular regression. The normal rat kidney microRNA profile resembled that of humans. MiR-34a was increased >7-fold and emerged as the predominant rat microRNA altered by radiation. Expression of Jagged1, a ligand in the Notch pathway of vascular development and a target of miR-34a-5p was decreased by radiation but not in irradiated rats receiving lisinopril. Radiation decreased endothelial cells in the kidneys at 100 days, confirming vascular regression. In conclusion, the results of this study showed that radiation greatly increased miRNA34-a in rat kidneys, while lisinopril mitigated radiation-induced decrease of the Notch ligand, Jagged1, a molecular target of miRNA34-a.
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http://dx.doi.org/10.1667/RADE-20-00078.1DOI Listing
July 2021

DEPTOR inhibits lung tumorigenesis by inactivating the EGFR-mTOR signals.

Cancer Lett 2021 Oct 25;519:263-276. Epub 2021 Jul 25.

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China. Electronic address:

DEPTOR plays vital roles in the regulation of cell proliferation and survival by directly modulating the activity of mTORC1/2. However, the physiological role of DEPTOR in lung tumorigenesis, as well as its clinical significance, remains elusive. In this study, we revealed that decreased DEPTOR expression correlated with increased tumor size, poor differentiation, and worse survival in patients with lung cancer. DEPTOR depletion promoted cell proliferation, survival, migration, and invasion in human lung cancer cells. Mechanistically, DEPTOR bound to the kinase domain of EGFR via its PDZ domain to inactivate EGFR signal. Thus, DEPTOR depletion not only directly activated mTORC1/2, but also relieved the inhibition of EGFR to subsequently activate mTOR signals, leading to the induction of cell proliferation and survival. Additionally, activated EGFR-mTOR signals upregulated the expression of ZEB1 and SLUG to induce epithelial-mesenchymal transition, resulting in enhanced migration and invasion. Importantly, Deptor deletion accelerated Kras;p53-induced lung tumorigenesis and shortened mouse life span via the activation of EGFR-mTOR signals. Collectively, our study demonstrated that DEPTOR acts as a tumor suppressor in lung tumorigenesis, and its reduction may advance the progression of human lung cancer.
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http://dx.doi.org/10.1016/j.canlet.2021.07.031DOI Listing
October 2021

Global identification and characterization of tRNA-derived RNA fragment landscapes across human cancers.

NAR Cancer 2020 Dec 19;2(4):zcaa031. Epub 2020 Oct 19.

Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.

Transfer RNA-derived RNA fragments (tRFs) are a class of small non-coding RNAs that are abundant in many organisms, but their role in cancer has not been fully explored. Here, we report a functional genomic landscape of tRFs in 8118 specimens across 15 cancer types from The Cancer Genome Atlas. These tRFs exhibited characteristics of widespread expression, high sequence conservation, cytoplasmic localization, specific patterns of tRNA cleavage and conserved cleavage in tissues. A cross-tumor analysis revealed significant commonality among tRF expression subtypes from distinct tissues of origins, characterized by upregulation of a group of tRFs with similar size and activation of cancer-associated signaling. One of the largest superclusters was composed of 22 nt 3'-tRFs upregulated in 13 cancer types, all of which share the activation of Ras/MAPK, RTK and TSC/mTOR signaling. tRF-based subgrouping provided clinically relevant stratifications and significantly improved outcome prediction by incorporating clinical variables. Additionally, we discovered 11 cancer driver tRFs using an effective approach for accurately exploring cross-tumor and platform trends. As a proof of concept, we performed comprehensive functional assays on a non-microRNA driver tRF, 5'-IleAAT-8-1-L20, and validated its oncogenic roles in lung cancer and . Our study also provides a valuable tRF resource for identifying diagnostic and prognostic biomarkers, developing cancer therapy and studying cancer pathogenesis.
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http://dx.doi.org/10.1093/narcan/zcaa031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210304PMC
December 2020

LCAT3, a novel m6A-regulated long non-coding RNA, plays an oncogenic role in lung cancer via binding with FUBP1 to activate c-MYC.

J Hematol Oncol 2021 07 17;14(1):112. Epub 2021 Jul 17.

Center for Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.

Background: Long non-coding RNAs (lncRNAs) are important epigenetic regulators, which play critical roles in diverse physiological and pathological processes. However, the regulatory mechanism of lncRNAs in lung carcinogenesis remains elusive. Here, we characterized a novel oncogenic lncRNA, designated as Lung Cancer Associated Transcript 3 (LCAT3).

Methods: We predicted and validated LCAT3 by analyzing RNA-sequencing (RNA-seq) data of lung cancer tissues from TCGA. Methylated RNA immunoprecipitation was performed to assess m6A modification on LCAT3. The LCAT3-FUBP1-MYC axis was assessed by dual-luciferase reporter, RNA immunoprecipitation and Chromatin immunoprecipitation assays. Signaling pathways altered by LCAT3 knockdown were identified using RNA-seq. Furthermore, the mechanism of LCAT3 was investigated using loss-of-function and gain-of-function assays in vivo and in vitro.

Results: LCAT3 was found to be up-regulated in lung adenocarcinomas (LUAD), and its over-expression was associated with the poor prognosis of LUAD patients. LCAT3 upregulation is attributable to N6-methyladenosine (m6A) modification mediated by methyltransferase like 3 (METTL3), leading to LCAT3 stabilization. Biologically, loss-of-function assays revealed that LCAT3 knockdown significantly suppressed lung cancer cell proliferation, migration and invasion in vitro, and inhibited tumor growth and metastasis in vivo. LCAT3 knockdown induced cell cycle arrest at the G1 phase. Mechanistically, LCAT3 recruited Far Upstream Element Binding Protein 1 (FUBP1) to the MYC far-upstream element (FUSE) sequence, thereby activating MYC transcription to promote proliferation, survival, invasion and metastasis of lung cancer cells.

Conclusions: Taken together, we identified and characterized LCAT3 as a novel oncogenic lncRNA in the lung, and validated the LCAT3-FUBP1-MYC axis as a potential therapeutic target for LUAD.
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http://dx.doi.org/10.1186/s13045-021-01123-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285886PMC
July 2021

Dietary Sodium Restriction Results in Tissue-Specific Changes in DNA Methylation in Humans.

Hypertension 2021 Aug 14;78(2):434-446. Epub 2021 Jun 14.

Department of Physiology, Center of Systems Molecular Medicine (X.P., C.Y., P.L., M.L.R., Y. Li, A.M.B., Yong Liu, A.W.C., D.L.M., M.L.), Medical College of Wisconsin, Milwaukee.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.17351DOI Listing
August 2021

An integrated epigenomic-transcriptomic landscape of lung cancer reveals novel methylation driver genes of diagnostic and therapeutic relevance.

Theranostics 2021 11;11(11):5346-5364. Epub 2021 Mar 11.

Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.

Aberrant DNA methylation occurs commonly during carcinogenesis and is of clinical value in human cancers. However, knowledge of the impact of DNA methylation changes on lung carcinogenesis and progression remains limited. Genome-wide DNA methylation profiles were surveyed in 18 pairs of tumors and adjacent normal tissues from non-small cell lung cancer (NSCLC) patients using Reduced Representation Bisulfite Sequencing (RRBS). An integrated epigenomic-transcriptomic landscape of lung cancer was depicted using the multi-omics data integration method. We discovered a large number of hypermethylation events pre-marked by poised promoter in embryonic stem cells, being a hallmark of lung cancer. These hypermethylation events showed a high conservation across cancer types. Eight novel driver genes with aberrant methylation (e.g., PCDH17 and IRX1) were identified by integrated analysis of DNA methylome and transcriptome data. Methylation level of the eight genes measured by pyrosequencing can distinguish NSCLC patients from lung tissues with high sensitivity and specificity in an independent cohort. Their tumor-suppressive roles were further experimentally validated in lung cancer cells, which depend on promoter hypermethylation. Similarly, 13 methylation-driven ncRNAs (including 8 lncRNAs and 5 miRNAs) were identified, some of which were co-regulated with their host genes by the same promoter hypermethylation. Finally, by analyzing the transcription factor (TF) binding motifs, we uncovered sets of TFs driving the expression of epigenetically regulated genes and highlighted the epigenetic regulation of gene expression of TCF21 through DNA methylation of EGR1 binding motifs. We discovered several novel methylation driver genes of diagnostic and therapeutic relevance in lung cancer. Our findings revealed that DNA methylation in TF binding motifs regulates target gene expression by affecting the binding ability of TFs. Our study also provides a valuable epigenetic resource for identifying DNA methylation-based diagnostic biomarkers, developing cancer drugs for epigenetic therapy and studying cancer pathogenesis.
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http://dx.doi.org/10.7150/thno.58385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039961PMC
July 2021

Nuclear ErbB2 represses DEPTOR transcription to inhibit autophagy in breast cancer cells.

Cell Death Dis 2021 04 14;12(4):397. Epub 2021 Apr 14.

Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

ErbB2, a classical receptor tyrosine kinase, is frequently overexpressed in breast cancer cells. Although the role of ErbB2 in the transmission of extracellular signals to intracellular matrix has been widely studied, the functions of nuclear ErbB2 remain largely elusive. Here, we report a novel function of nuclear ErbB2 in repressing the transcription of DEPTOR, a direct inhibitor of mTOR. Nuclear ErbB2 directly binds to the consensus binding sequence in the DEPTOR promoter to repress its transcription. The kinase activity of ErbB2 is required for its nuclear translocation and transcriptional repression of DEPTOR. Moreover, the repressed DEPTOR by nuclear ErbB2 inhibits the induction of autophagy by activating mTORC1. Thus, our study reveals a novel mechanism for autophagy regulation by functional ErbB2, which translocates to the nucleus and acts as a transcriptional regulator to suppress DEPTOR transcription, leading to activation of the PI3K/AKT/mTOR pathway to inhibit autophagy.
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http://dx.doi.org/10.1038/s41419-021-03686-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047043PMC
April 2021

Integrated analysis of virus and host transcriptomes in cervical cancer in Asian and Western populations.

Genomics 2021 May 27;113(3):1554-1564. Epub 2021 Mar 27.

Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China. Electronic address:

Race may influence vulnerability to HPV variants in viral infection and perisistence. Integrated analysis of the virus and host transcriptomes from different populations provides an unprecedented opportunity to understand these racial disparities in the prevalence of HPV and cervical cancers. We performed RNA-Seq analysis of 90 tumors and 39 adjacent normal tissues from cervical cancer patients at Zhejiang University (ZJU) in China, and conducted a comparative analysis with RNA-Seq data of 286 cervical cancers from TCGA. We found a modestly higher rate of HPV positives and HPV integrations in TCGA than in ZJU. In addition to LINC00393 and HSPB3 as new common integration hotspots in both cohorts, we found new hotspots such as SH2D3C and CASC8 in TCGA, and SCGB1A1 and ABCA1 in ZJU. We described the first, to our knowledge, virus-transcriptome-based classification of cervical cancer associated with clinical outcome. Particularly, patients with expressed E5 performed better than those without E5 expression. However, the constituents of these virus-transcriptome-based tumor subtypes differ dramatically between the two cohorts. We further characterized the immune infiltration landscapes between different HPV statuses and revealed significantly elevated levels of regulatory T cells and M0 macrophages in HPV positive tumors, which were associated with poor prognosis. These findings increase our understanding of the racial disparities in the prevalence of HPV and its associated cervical cancers between the two cohorts, and also have important implications in the classification of tumor subtypes, prognosis, and anti-cancer immunotherapy in cervical cancer.
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http://dx.doi.org/10.1016/j.ygeno.2021.03.029DOI Listing
May 2021

Plasma-derived exosomal miR-15a-5p as a promising diagnostic biomarker for early detection of endometrial carcinoma.

Mol Cancer 2021 03 29;20(1):57. Epub 2021 Mar 29.

Department of Gynecologic Oncology, Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.

Endometrial cancer (EC) is a major cause of death among gynecologic malignancies. To improve early detection of EC in patients, we carried out a large plasma-derived exosomal microRNA (miRNA) studies for diagnostic biomarker discovery in EC. Small RNA sequencing was performed to identify candidate exosomal miRNAs as diagnostic biomarkers in 56 plasma samples from healthy subjects and EC patients. These miRNA candidates were further validated in 202 independent plasma samples by droplet digital PCR (ddPCR), 32 pairs of endometrial tumors and adjacent normal tissues by quantitative real-time PCR (qRT-PCR), and matched plasma samples of 12 patients before and after surgery by ddPCR. miR-15a-5p, miR-106b-5p, and miR107 were significantly upregulated in exomes isolated from plasma samples of EC patients compared with healthy subjects. Particularly, miR-15a-5p alone yielded an AUC value of 0.813 to distinguish EC patients with stage I from healthy subjects. The integration of miR-15a-5p and serum tumor markers (CEA and CA125) achieved a higher AUC value of 0.899. There was also a close connection between miR-15a-5p and clinical manifestations in EC patients. Its exosomal expression was not only associated with the depth of muscular infiltration and aggressiveness of EC, but also correlated with levels of reproductive hormones such as TTE and DHEAS. Collectively, plasma-derived exosomal miR-15a-5p is a promising and effective diagnostic biomarker for the early detection of endometrial cancer.
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http://dx.doi.org/10.1186/s12943-021-01352-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006369PMC
March 2021

Transfer RNA Fragments in the Kidney in Hypertension.

Hypertension 2021 May 29;77(5):1627-1637. Epub 2021 Mar 29.

Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee (X.P., X.G., Y.L., M.K.M., P.L., M.L.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.16994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370717PMC
May 2021

Divergent Patterns of Bacterial Community Structure and Function in Response to Estuarine Output in the Middle of the Bohai Sea.

Front Microbiol 2021 8;12:630741. Epub 2021 Mar 8.

Key Laboratory of Coastal Biology and Bioresource Utilization, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, China.

Understanding environment-community relationships under shifting environmental conditions helps uncover mechanisms by which environmental microbial communities manage to improve ecosystem functioning. This study investigated the microbial community and structure near the Yellow Sea River estuary in 12 stations across the middle of the Bohai Sea for over two seasons to elucidate the influence of estuarine output on them. We found that the dominant phyla in all stations were Proteobacteria, Cyanobacteria, Bacteroidetes, Actinobacteria, and Planctomycetes. Alpha-diversity increased near the estuary and bacterial community structure differed with variation of spatiotemporal gradients. Among all the environmental factors surveyed, temperature, salinity, phosphate, silicon, nitrate, and total virioplankton abundance played crucial roles in controlling the bacterial community composition. Some inferred that community functions such as carbohydrate, lipid, amino acid metabolism, xenobiotics biodegradation, membrane transport, and environmental adaptation were much higher in winter; energy and nucleotide metabolism were lower in winter. Our results suggested that estuarine output had a great influence on the Bohai Sea environment and changes in the water environmental conditions caused by estuarine output developed distinctive microbial communities in the middle of the Bohai Sea. The distinctive microbial communities in winter demonstrated that the shifting water environment may stimulate changes in the diversity and then strengthen the predicted functions.
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http://dx.doi.org/10.3389/fmicb.2021.630741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982528PMC
March 2021

Corrigendum to article "DriverML: a machine learning algorithm for identifying driver genes in cancer sequencing studies''.

Nucleic Acids Res 2021 04;49(7):4196

Center for Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.

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http://dx.doi.org/10.1093/nar/gkab193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053120PMC
April 2021

Characteristics of bacterial community structure and function associated with nutrients and heavy metals in coastal aquaculture area.

Environ Pollut 2021 Apr 2;275:116639. Epub 2021 Feb 2.

Key Laboratory of Coastal Biology and Bioresource Utilization, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, 264403, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266237, China. Electronic address:

Coastal aquaculture area has become one of the critical zones that are more susceptible to the influence of human activity. Many aquaculture operations invariably result in the accumulation of nutrients and heavy metals in the coastal ecosystem. Our study investigated sediment bacterial community structure and function across 23 sites under the influence of nutrients and heavy metals in the coastal aquaculture area. The habitat environment of the sediment was described by analyzing physicochemical characteristics. Sediment bacterial community structure and diversity were investigated by 16S rRNA sequencing. The sequencing data presented that Proteobacteria, Bacteroidetes, Planctomycetes, Acidobacteria and Chloroflexi were predominant at phylum level. Variations in the bacterial community composition and diversity were significant (P < 0.01) among different groups (according to the distance from the bank side) which indicated that specific environmental conditions had shaped distinct bacterial community. Specifically, bacterial diversity and composition were significantly influenced by the temperature, salinity, pH, dissolved oxygen (DO), TOC, TON, nitrite, nitrate and heavy metals (P < 0.05). Results related to functional prediction demonstrated that carbon, nitrogen and sulfur metabolism were the dominant processes in the coastal aquaculture area. In the meantime, the potential pathogens such as Arcobacter was found in site S3, which indicated the possible threat to the cultured species in this area. Overall, variations in bacterial communities caused by nutrients and heavy metals can affect biogeochemical cycles, which may provide an indication for the protection of coastal aquaculture environments.
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http://dx.doi.org/10.1016/j.envpol.2021.116639DOI Listing
April 2021

Alternative polyadenylation: methods, mechanism, function, and role in cancer.

J Exp Clin Cancer Res 2021 Feb 1;40(1):51. Epub 2021 Feb 1.

Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China.

Occurring in over 60% of human genes, alternative polyadenylation (APA) results in numerous transcripts with differing 3'ends, thus greatly expanding the diversity of mRNAs and of proteins derived from a single gene. As a key molecular mechanism, APA is involved in various gene regulation steps including mRNA maturation, mRNA stability, cellular RNA decay, and protein diversification. APA is frequently dysregulated in cancers leading to changes in oncogenes and tumor suppressor gene expressions. Recent studies have revealed various APA regulatory mechanisms that promote the development and progression of a number of human diseases, including cancer. Here, we provide an overview of four types of APA and their impacts on gene regulation. We focus particularly on the interaction of APA with microRNAs, RNA binding proteins and other related factors, the core pre-mRNA 3'end processing complex, and 3'UTR length change. We also describe next-generation sequencing methods and computational tools for use in poly(A) signal detection and APA repositories and databases. Finally, we summarize the current understanding of APA in cancer and provide our vision for future APA related research.
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http://dx.doi.org/10.1186/s13046-021-01852-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852185PMC
February 2021

Seagrass vegetation affect the vertical organization of microbial communities in sediment.

Mar Environ Res 2020 Dec 7;162:105174. Epub 2020 Oct 7.

Key Laboratory of Coastal Biology and Bioresource Utilization, Yantai Institute of Costal Zone Research, Chinese Academy of Sciences, Yantai, Shandong, 264003, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, Shandong, 266237, China. Electronic address:

Seagrasses represent high primary productivity and provide important ecosystem services to the marine environment. Seagrass-associated microbial communities are playing essential ecological functional roles in biogeochemical cycles. However, little is known about the effect of seagrass vegetation on microbial communities in sediment. In the present study, the sediment cores of seagrass bed (dominated by Zostera japonica and Zostera marine) and degradation area in Swan Lake (China) were sampled; then, biogeochemical parameters were analyzed, and microbial community composition was investigated by using high-throughput sequencing of the 16S rRNA gene. The results showed that the presence of seagrass could lead to a decrease in the richness and diversity of the microbial community. In the vertical direction, a pronounced shift from Proteobacteria-dominated upper layers to Chloroflexi and Crenarchaeota-dominated deep layers in all sediment cores were observed. Besides, Bathyarchaeia is more abundant at degradation area, while Vibrionaceae, Sulfurovum and Lokiarchaeial overrepresent at the seagrass bed area. Vibrionaceae was abundant in the rhizosphere of Z. marina and Z. japonica, and the proportions reached 84.45% and 63.89%, respectively. This enrichment of Vibrio spp. may be caused by the macrobenthic species near the seagrass rhizosphere, and these Vibrio spp. reduced the diversity and stability of microbial community, which may lead to the degradation of seagrass. This study would provide clues for the distribution patterns and niche preferences of seagrass microbiome. The conservation strategy of seagrass would be further elucidated from the perspective of the microbiome.
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http://dx.doi.org/10.1016/j.marenvres.2020.105174DOI Listing
December 2020

tRNA-derived RNA fragments in cancer: current status and future perspectives.

J Hematol Oncol 2020 09 4;13(1):121. Epub 2020 Sep 4.

Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Non-coding RNAs (ncRNAs) have been the focus of many studies over the last few decades, and their fundamental roles in human diseases have been well established. Transfer RNAs (tRNAs) are housekeeping ncRNAs that deliver amino acids to ribosomes during protein biosynthesis. tRNA fragments (tRFs) are a novel class of small ncRNAs produced through enzymatic cleavage of tRNAs and have been shown to play key regulatory roles similar to microRNAs. Development and application of high-throughput sequencing technologies has provided accumulating evidence of dysregulated tRFs in cancer. Aberrant expression of tRFs has been found to participate in cell proliferation, invasive metastasis, and progression in several human malignancies. These newly identified functional tRFs also have great potential as new biomarkers and therapeutic targets for cancer treatment. In this review, we focus on the major biological functions of tRFs including RNA silencing, translation regulation, and epigenetic regulation; summarize recent research on the roles of tRFs in different types of cancer; and discuss the potential of using tRFs as clinical biomarkers for cancer diagnosis and prognosis and as therapeutic targets for cancer treatment.
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http://dx.doi.org/10.1186/s13045-020-00955-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487644PMC
September 2020

Prophylactic chemotherapeutic hyperthermic intraperitoneal perfusion reduces peritoneal metastasis in gastric cancer: a retrospective clinical study.

BMC Cancer 2020 Aug 31;20(1):827. Epub 2020 Aug 31.

Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, P.R. China.

Background: Peritoneal metastasis is the most frequent failure in gastric cancer. This study evaluated the role of prophylactic chemotherapeutic hyperthermic intraperitoneal perfusion (CHIP) in patients after D2 dissection.

Methods: Gastric cancer patients after D2 dissection were enrolled in this study. Patients received either chemotherapy (IV group) or CHIP (CHIP group). Sites of recurrence or metastasis, disease-free survival (DFS), overall survival (OS) and adverse events were evaluated.

Results: Twenty-two patients received CHIP treatment, and 21 patients received chemotherapy alone. The median DFS time was 24.5 and 36.5 months in the IV group and CHIP group (P = 0.044), respectively. The median OS time was 33.1 months in the IV group and not reached in the CHIP group (P = 0.037). We also found that CHIP could reduce the total recurrence/metastasis rate, especially that of peritoneal metastasis. In the subgroup analysis, DFS and OS were both superior in deficient mismatch repair (dMMR) patients than in proficient MMR (pMMR) patients.

Conclusion: This hypothesis-generating study indicates that CHIP might be feasible for gastric cancer patients after D2 resection.
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http://dx.doi.org/10.1186/s12885-020-07339-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461269PMC
August 2020

β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion.

J Exp Med 2020 11;217(11)

Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.

PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Here, we show that Wnt ligand and activated EGFR induce the binding of the β-catenin/TCF/LEF complex to the CD274 gene promoter region to induce PD-L1 expression, in which AKT activation plays an important role. β-Catenin depletion, AKT inhibition, or PTEN expression reduces PD-L1 expression in tumor cells, enhances activation and tumor infiltration of CD8+ T cells, and reduces tumor growth, accompanied by prolonged mouse survival. Combined treatment with a clinically available AKT inhibitor and an anti-PD-1 antibody overcomes tumor immune evasion and greatly inhibits tumor growth. In addition, AKT-mediated β-catenin S552 phosphorylation and nuclear β-catenin are positively correlated with PD-L1 expression and inversely correlated with the tumor infiltration of CD8+ T cells in human glioblastoma specimens, highlighting the clinical significance of β-catenin activation in tumor immune evasion.
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http://dx.doi.org/10.1084/jem.20191115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596815PMC
November 2020

A comprehensive evaluation of computational tools to identify differential methylation regions using RRBS data.

Genomics 2020 11 24;112(6):4567-4576. Epub 2020 Jul 24.

Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address:

DNA methylation plays a vital role in transcription regulation. Reduced representation bisulfite sequencing (RRBS) is becoming common for analyzing genome-wide methylation profiles at the single nucleotide level. A major goal of RRBS studies is to detect differentially methylated regions (DMRs) between different biological conditions. The previous tools to predict DMRs lack consistency. Here, we simulated RRBS datasets with significant attributes of real sequencing data under a wide range of scenarios, and systematically evaluated seven DMR detection tools in terms of type I error rate, precision/recall (PR), and area under ROC curve (AUC) using different methylation levels, sequencing coverage depth, length of DMRs, read length, and sample sizes. DMRfinder, methylSig, and methylKit were our preferred tools for RRBS data analysis, in terms of their AUC and PR curves. Our comparison highlights the different applicability of DMR detection tools and provides information to guide researchers towards the advancement of sequence-based DMR analysis.
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http://dx.doi.org/10.1016/j.ygeno.2020.07.032DOI Listing
November 2020

The Zscan4-Tet2 Transcription Nexus Regulates Metabolic Rewiring and Enhances Proteostasis to Promote Reprogramming.

Cell Rep 2020 07;32(2):107877

Huashan Hospital, Fudan University, and Molecular and Cell Biology Lab, the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, and the Key Laboratory of Metabolism and Molecular, Ministry of Education, Shanghai, China; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Beijing, China; Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address:

Evolutionarily conserved SCAN (named after SRE-ZBP, CTfin51, AW-1, and Number 18 cDNA)-domain-containing zinc finger transcription factors (ZSCAN) have been found in both mouse and human genomes. Zscan4 is transiently expressed during zygotic genome activation (ZGA) in preimplantation embryos and induced pluripotent stem cell (iPSC) reprogramming. However, little is known about the mechanism of Zscan4 underlying these processes of cell fate control. Here, we show that Zscan4f, a representative of ZSCAN proteins, is able to recruit Tet2 through its SCAN domain. The Zscan4f-Tet2 interaction promotes DNA demethylation and regulates the expression of target genes, particularly those encoding glycolytic enzymes and proteasome subunits. Zscan4f regulates metabolic rewiring, enhances proteasome function, and ultimately promotes iPSC generation. These results identify Zscan4f as an important partner of Tet2 in regulating target genes and promoting iPSC generation and suggest a possible and common mechanism shared by SCAN family transcription factors to recruit ten-eleven translocation (TET) DNA dioxygenases to regulate diverse cellular processes, including reprogramming.
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http://dx.doi.org/10.1016/j.celrep.2020.107877DOI Listing
July 2020

OncotRF: an online resource for exploration of tRNA-derived fragments in human cancers.

RNA Biol 2020 08 28;17(8):1081-1091. Epub 2020 Jun 28.

Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, School of Medicine, Zhejiang University , Hangzhou, Zhejiang, China.

Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs whose biological roles in cancers are not well understood. Emerging evidence suggests that tRFs are involved in gene regulation at multiple levels. In this study, we constructed an integrative database, OncotRF (http://bioinformatics.zju.edu.cn/OncotRF), for exploration of tRF functions, and identification of diagnostic and prognostic biomarkers in cancers. The database contains an analysis pipeline for tRF identification and characterization, analysis results of 11,211 small RNA sequencing samples and 8,776 RNA sequencing samples, and clinicopathologic annotation data from The Cancer Genome Atlas (TCGA). The results include: tRF identification and quantification across cancers, abnormally expressed tRFs and genes, tRF-gene correlations, tRF-gene networks, survival analyses, and tRF-related functional enrichment analyses. Users are also able to identify differentially expressed tRFs, predict their functions, and assess the relevance of the tRF expression levels to the clinical outcome according to user-defined groups. Additionally, an online Kaplan-Meier plotter is available in OncotRF for plotting survival curves according to user-defined groups. OncotRF will be a valuable online database and functional annotation tool for researchers studying the roles, functions, and mechanisms of tRFs in human cancers.
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http://dx.doi.org/10.1080/15476286.2020.1776506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577240PMC
August 2020

p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis.

Cancer Res 2020 08 24;80(16):3251-3264. Epub 2020 Jun 24.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.

KRAS is mutated in most pancreatic ductal adenocarcinomas (PDAC) and yet remains undruggable. Here, we report that p38γ MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38γ interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38γ increased expression of PFKFB3 and glucose transporter GLUT2, conversely, silencing mutant KRAS, and p38γ decreased PFKFB3 and GLUT2 expression. p38γ phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout of p38γ decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice. PFKFB3 and GLUT2 depended on p38γ to stimulate glycolysis and PDAC growth and p38γ required PFKFB3/S467 to promote these activities. A p38γ inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38γ. Moreover, overexpression of p38γ, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38γ links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38γ and PFKFB3 may be targeted for therapeutic intervention in PDAC. SIGNIFICANCE: These findings show that p38γ links KRAS oncogene signaling and the Warburg effect through PFKBF3 and Glut2 to promote pancreatic tumorigenesis, which can be disrupted via inhibition of p38γ and PFKFB3.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3281DOI Listing
August 2020

Epidemiological Assessment of Imported Coronavirus Disease 2019 (COVID-19) Cases in the Most Affected City Outside of Hubei Province, Wenzhou, China.

JAMA Netw Open 2020 04 1;3(4):e206785. Epub 2020 Apr 1.

Department of Gynecologic Oncology, Women's Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.6785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180422PMC
April 2020

Single-Cell Transcriptomic Analysis.

Compr Physiol 2020 03 12;10(2):767-783. Epub 2020 Mar 12.

Department of Gynecologic Oncology, Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Single-cell sequencing measures the sequence information from individual cells using optimized single-cell isolation protocols and next-generation sequencing technologies. Recent advancement in single-cell sequencing has transformed biomedical research, providing insights into diverse biological processes such as mammalian development, immune system function, cellular diversity and heterogeneity, and disease pathogenesis. In this article, we introduce and describe popular commercial platforms for single-cell RNA sequencing, general workflow for data analysis, repositories and databases, and applications for these approaches in biomedical research. © 2020 American Physiological Society. Compr Physiol 10:767-783, 2020.
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http://dx.doi.org/10.1002/cphy.c190037DOI Listing
March 2020

MDEHT: a multivariate approach for detecting differential expression of microRNA isoform data in RNA-sequencing studies.

Bioinformatics 2020 05;36(9):2657-2664

Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province and Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China.

Motivation: miRNA isoforms (isomiRs) are produced from the same arm as the archetype miRNA with a few nucleotides different at 5 and/or 3 termini. These well-conserved isomiRs are functionally important and have contributed to the evolution of miRNA genes. Accurate detection of differential expression of miRNAs can bring new insights into the cellular function of miRNA and a further improvement in miRNA-based diagnostic and prognostic applications. However, very few methods take isomiR variations into account in the analysis of miRNA differential expression.

Results: To overcome this challenge, we developed a novel approach to take advantage of the multidimensional structure of isomiR data from the same miRNAs, termed as a multivariate differential expression by Hotelling's T2 test (MDEHT). The utilization of the information hidden in isomiRs enables MDEHT to increase the power of identifying differentially expressed miRNAs that are not marginally detectable in univariate testing methods. We conducted rigorous and unbiased comparisons of MDEHT with seven commonly used tools in simulated and real datasets from The Cancer Genome Atlas. Our comprehensive evaluations demonstrated that the MDEHT method was robust among various datasets and outperformed other commonly used tools in terms of Type I error rate, true positive rate and reproducibility.

Availability And Implementation: The source code for identifying and quantifying isomiRs and performing miRNA differential expression analysis is available at https://github.com/amanzju/MDEHT.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203753PMC
May 2020

Comparative and Functional Genomic Resource for Mechanistic Studies of Human Blood Pressure-Associated Single Nucleotide Polymorphisms.

Hypertension 2020 03 6;75(3):859-868. Epub 2020 Jan 6.

From the Department of Physiology, Center of Systems Molecular Medicine (M.K.M., E.Y.L., A.M.G., P.L., A.S.G., M.L., Y.L.), Medical College of Wisconsin, Milwaukee.

The objective of the current study is to use comparative and functional genomic analysis to help to understand the biological mechanism mediating the effect of single nucleotide polymorphisms (SNPs) on blood pressure. We mapped 26 585 SNPs that are in linkage disequilibrium with 1071 human blood pressure-associated sentinel SNPs to 9447 syntenic regions in the mouse genome. Approximately 21.8% of the 1071 linkage disequilibrium regions are located at least 10 kb from any protein-coding gene. Approximately 300 blood pressure-associated SNPs are expression quantitative trait loci for a few dozen known blood pressure physiology genes in tissues including specific kidney regions. Blood pressure-associated sentinel SNPs are significantly enriched for expression quantitative trait loci for blood pressure physiology genes compared with randomly selected SNPs (<0.00023, Fisher exact test). Using a newly developed deep learning method and other methods, we identified SNPs that were predicted to influence the conservation of CTCF (CCCTC-binding factor) binding across cell types, transcription factor binding, mRNA splicing, or secondary structures of RNA including long noncoding RNA. The SNPs were more likely to be located in CTCF-binding regions than what would be expected from the whole genome (=4.90×10, Pearson χ test). One example synonymous SNP rs9337951 was predicted to influence the secondary structure of its host mRNA JCAD (junctional cadherin 5 associated) and was experimentally validated to influence JCAD protein expression. These findings provide an extensive comparative and functional genomic resource for developing experiments to test the functional significance of human blood pressure-associated SNPs in human cells and animal models.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035167PMC
March 2020

Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases.

Sci Rep 2019 12 18;9(1):19365. Epub 2019 Dec 18.

Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China.

Rare diseases are usually chronically debilitating or even life-threatening with diagnostic and therapeutic challenges in current clinical practice. It has been estimated that 80% of rare diseases are genetic in origin, and thus genome sequencing-based diagnosis offers a promising alternative for rare-disease management. In this study, 79 individuals from 16 independent families were performed for whole-genome sequencing (WGS) in an effort to identify the causative mutations for 16 distinct rare diseases that are largely clinically intractable. Comprehensive analysis of variations, including simple nucleotide variants (SNVs), copy-number variations (CNVs), and structural variations (SVs), was implemented using the WGS data. A flexible analysis pipeline that allowed a certain degree of misclassification of disease status was developed to facilitate the identification of causative variants. As a result, disease-causing variants were identified in 10 of the 16 investigated diseases, yielding a diagnostic rate of 62.5%. Additionally, new potentially pathogenic variants were discovered for two disorders, including IGF2/INS-IGF2 in mitochondrial disease and FBN3 in Klippel-Trenaunay-Weber syndrome. Our WGS analysis not only detected a CNV associated with 3p deletion syndrome but also captured a simple sequence repeat (SSR) variation associated with Machado-Joseph disease. To our knowledge, this is the first time the clinical WGS analysis of short-read sequences has been used successfully to identify a causative SSR variation that perfectly segregates with a repeat expansion disorder. After the WGS analysis, we confirmed the initial diagnosis for three of 10 established disorders and modified or corrected the initial diagnosis for the remaining seven disorders. In summary, clinical WGS is a powerful tool for the diagnosis of rare diseases, and its diagnostic clarity at molecular levels offers important benefits for the participating families.
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http://dx.doi.org/10.1038/s41598-019-55832-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920370PMC
December 2019

Epigenetic Modifications in T Cells: The Role of DNA Methylation in Salt-Sensitive Hypertension.

Hypertension 2020 02 16;75(2):372-382. Epub 2019 Dec 16.

From the Departments of Physiology (J.H.D., A.J.A., J.M.A.-B., X.P., D.J.F., H.L., M.L.R., A.W.C., P.L., M.L., D.L.M.), Medical College of Wisconsin Milwaukee, Wisconsin, USA.

The SS (Dahl salt sensitive) rat is an established model of hypertension and renal damage that is accompanied with immune system activation in response to a high-salt diet. Investigations into the effects of sodium-independent and dependent components of the diet were shown to affect the disease phenotype with SS/MCW (JrHsdMcwi) rats maintained on a purified diet (AIN-76A) presenting with a more severe phenotype relative to grain-fed SS/CRL (JrHsdMcwiCrl) rats. Since contributions of the immune system, environment, and diet are documented to alter this phenotype, this present study examined the epigenetic profile of T cells isolated from the periphery and the kidney from these colonies. T cells isolated from kidneys of the 2 colonies revealed that transcriptomic and functional differences may contribute to the susceptibility of hypertension and renal damage. In response to high-salt challenge, the methylome of T cells isolated from the kidney of SS/MCW exhibit a significant increase in differentially methylated regions with a preference for hypermethylation compared with the SS/CRL kidney T cells. Circulating T cells exhibited similar methylation profiles between colonies. Utilizing transcriptomic data from T cells isolated from the same animals upon which the DNA methylation analysis was performed, a predominant negative correlation was observed between gene expression and DNA methylation in all groups. Lastly, inhibition of DNA methyltransferases blunted salt-induced hypertension and renal damage in the SS/MCW rats providing a functional role for methylation. This study demonstrated the influence of epigenetic modifications to immune cell function, highlighting the need for further investigations.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058976PMC
February 2020
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