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Role of Long Non-coding RNAs in Reprogramming to Induced Pluripotency.

Shahzina KANWAL ; Xiangpeng GUO ; Carl WARD ; Giacomo VOLPE ; Baoming QIN ; Miguel A ESTEBAN ; Xichen BAO

Genomics, Proteomics & Bioinformatics.2020;18(1):16-25. doi:10.1016/j.gpb.2019.06.003

The generation of induced pluripotent stem cells through somatic cell reprogramming requires a global reorganization of cellular functions. This reorganization occurs in a multi-phased manner and involves a gradual revision of both the epigenome and transcriptome. Recent studies have shown that the large-scale transcriptional changes observed during reprogramming also apply to long non-coding RNAs (lncRNAs), a type of traditionally neglected RNA species that are increasingly viewed as critical regulators of cellular function. Deeper understanding of lncRNAs in reprogramming may not only help to improve this process but also have implications for studying cell plasticity in other contexts, such as development, aging, and cancer. In this review, we summarize the current progress made in profiling and analyzing the role of lncRNAs in various phases of somatic cell reprogramming, with emphasis on the re-establishment of the pluripotency gene network and X chromosome reactivation.

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The Birth of Bio-data Science: Trends, Expectations, and Applications.

Wilson Wen Bin GOH ; Limsoon WONG

Genomics, Proteomics & Bioinformatics.2020;18(1):5-15. doi:10.1016/j.gpb.2020.01.002

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SinoDuplex: An Improved Duplex Sequencing Approach to Detect Low-frequency Variants in Plasma cfDNA Samples.

Yongzhe REN ; Yang ZHANG ; Dandan WANG ; Fengying LIU ; Ying FU ; Shaohua XIANG ; Li SU ; Jiancheng LI ; Heng DAI ; Bingding HUANG

Genomics, Proteomics & Bioinformatics.2020;18(1):81-90. doi:10.1016/j.gpb.2020.02.003

Accurate detection of low frequency mutations from plasma cell-free DNA in blood using targeted next generation sequencing technology has shown promising benefits in clinical settings. Duplex sequencing technology is the most commonly used approach in liquid biopsies. Unique molecular identifiers are attached to each double-stranded DNA template, followed by production of low-error consensus sequences to detect low frequency variants. However, high sequencing costs have hindered application of this approach in clinical practice. Here, we have developed an improved duplex sequencing approach called SinoDuplex, which utilizes a pool of adapters containing pre-defined barcode sequences to generate far fewer barcode combinations than with random sequences, and implemented a novel computational analysis algorithm to generate duplex consensus sequences more precisely. SinoDuplex increased the output of duplex sequencing technology, making it more cost-effective. We evaluated our approach using reference standard samples and cell-free DNA samples from lung cancer patients. Our results showed that SinoDuplex has high sensitivity and specificity in detecting very low allele frequency mutations. The source code for SinoDuplex is freely available at https://github.com/SinOncology/sinoduplex.

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CRISPR Screens Identify Essential Cell Growth Mediators in BRAF Inhibitor-resistant Melanoma.

Ziyi LI ; Binbin WANG ; Shengqing GU ; Peng JIANG ; Avinash SAHU ; Chen-Hao CHEN ; Tong HAN ; Sailing SHI ; Xiaoqing WANG ; Nicole TRAUGH ; Hailing LIU ; Yin LIU ; Qiu WU ; Myles BROWN ; Tengfei XIAO ; Genevieve M BOLAND ; X SHIRLEY LIU

Genomics, Proteomics & Bioinformatics.2020;18(1):26-40. doi:10.1016/j.gpb.2020.02.002

BRAF is a serine/threonine kinase that harbors activating mutations in ∼7% of human malignancies and ∼60% of melanomas. Despite initial clinical responses to BRAF inhibitors, patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAF inhibitor resistant melanoma, we conduct CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAF inhibitors. To investigate the mechanisms and pathways enabling resistance to BRAF inhibitors in melanomas, we integrate expression, ATAC-seq, and CRISPR screen data. We identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6, which together enable resistance to BRAF inhibitors in melanoma cells. Our findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720, providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.

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Procleave: Predicting Protease-specific Substrate Cleavage Sites by Combining Sequence and Structural Information.

Fuyi LI ; Andre LEIER ; Quanzhong LIU ; Yanan WANG ; Dongxu XIANG ; Tatsuya AKUTSU ; Geoffrey I WEBB ; A Ian SMITH ; Tatiana MARQUEZ-LAGO ; Jian LI ; Jiangning SONG

Genomics, Proteomics & Bioinformatics.2020;18(1):52-64. doi:10.1016/j.gpb.2019.08.002

Proteases are enzymes that cleave and hydrolyse the peptide bonds between two specific amino acid residues of target substrate proteins. Protease-controlled proteolysis plays a key role in the degradation and recycling of proteins, which is essential for various physiological processes. Thus, solving the substrate identification problem will have important implications for the precise understanding of functions and physiological roles of proteases, as well as for therapeutic target identification and pharmaceutical applicability. Consequently, there is a great demand for bioinformatics methods that can predict novel substrate cleavage events with high accuracy by utilizing both sequence and structural information. In this study, we present Procleave, a novel bioinformatics approach for predicting protease-specific substrates and specific cleavage sites by taking into account both their sequence and 3D structural information. Structural features of known cleavage sites were represented by discrete values using a LOWESS data-smoothing optimization method, which turned out to be critical for the performance of Procleave. The optimal approximations of all structural parameter values were encoded in a conditional random field (CRF) computational framework, alongside sequence and chemical group-based features. Here, we demonstrate the outstanding performance of Procleave through extensive benchmarking and independent tests. Procleave is capable of correctly identifying most cleavage sites in the case study. Importantly, when applied to the human structural proteome encompassing 17,628 protein structures, Procleave suggests a number of potential novel target substrates and their corresponding cleavage sites of different proteases. Procleave is implemented as a webserver and is freely accessible at http://procleave.erc.monash.edu/.

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The Elements of Data Sharing.

Zhang ZHANG ; Shuhui SONG ; Jun YU ; Wenming ZHAO ; Jingfa XIAO ; Yiming BAO

Genomics, Proteomics & Bioinformatics.2020;18(1):1-4. doi:10.1016/j.gpb.2020.04.001

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Mapping Genome Variants Sheds Light on Genetic and Phenotypic Differentiation in Chinese.

Li GUO ; Kai YE

Genomics, Proteomics & Bioinformatics.2019;17(3):226-228. doi:10.1016/j.gpb.2019.09.001

Asian Continental Ancestry Group ; Cell Differentiation ; Genome ; Humans

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Novel Autoantibodies Related to Cell Death and DNA Repair Pathways in Systemic Lupus Erythematosus.

Hui LUO ; Ling WANG ; Ding BAO ; Li WANG ; Hongjun ZHAO ; Yun LIAN ; Mei YAN ; Chandra MOHAN ; Quan-Zhen LI

Genomics, Proteomics & Bioinformatics.2019;17(3):248-259. doi:10.1016/j.gpb.2018.11.004

Systemic lupus erythematosus (SLE) is a complex autoimmune syndrome characterized by various co-existing autoantibodies (autoAbs) in patients' blood. However, the full spectrum of autoAbs in SLE has not been comprehensively elucidated. In this study, a commercial platform bearing 9400 antigens (ProtoArray) was used to identify autoAbs that were significantly elevated in the sera of SLE patients. By comparing the autoAb profiles of SLE patients with those of healthy controls, we identified 437 IgG and 1213 IgM autoAbs that the expression levels were significantly increased in SLE (P < 0.05). Use of the ProtoArray platform uncovered over 300 novel autoAbs targeting a broad range of nuclear, cytoplasmic, and membrane antigens. Molecular interaction network analysis revealed that the antigens targeted by the autoAbs were most significantly enriched in cell death, cell cycle, and DNA repair pathways. A group of autoAbs associated with cell apoptosis and DNA repair function, including those targeting APEX1, AURKA, POLB, AGO1, HMGB1, IFIT5, MAPKAPK3, PADI4, RGS3, SRP19, UBE2S, and VRK1, were further validated by ELISA and Western blot in a larger cohort. In addition, the levels of autoAbs against APEX1, HMGB1, VRK1, AURKA, PADI4, and SRP19 were positively correlated with the level of anti-dsDNA in SLE patients. Comprehensive autoAb screening has identified novel autoAbs, which may shed light on potential pathogenic pathways leading to lupus.

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Diversified Application of Barcoded PLATO (PLATO-BC) Platform for Identification of Protein Interactions.

Weili KONG ; Tsuyoshi HAYASHI ; Guillaume FICHES ; Qikai XU ; Mamie Z LI ; Jianwen QUE ; Shuai LIU ; Wei ZHANG ; Jun QI ; Netty SANTOSO ; Stephen J ELLEDGE ; Jian ZHU

Genomics, Proteomics & Bioinformatics.2019;17(3):319-331. doi:10.1016/j.gpb.2018.12.010

Proteins usually associate with other molecules physically to execute their functions. Identifying these interactions is important for the functional analysis of proteins. Previously, we reported the parallel analysis of translated ORFs (PLATO) to couple ribosome display of full-length ORFs with affinity enrichment of mRNA/protein/ribosome complexes for the "bait" molecules, followed by the deep sequencing analysis of mRNA. However, the sample processing, from extraction of precipitated mRNA to generation of DNA libraries, includes numerous steps, which is tedious and may cause the loss of materials. Barcoded PLATO (PLATO-BC), an improved platform was further developed to test its application for protein interaction discovery. In this report, we tested the antisera-antigen interaction using serum samples from patients with inclusion body myositis (IBM). Tripartite motif containing 21 (TRIM21) was identified as a potentially new IBM autoantigen. We also expanded the application of PLATO-BC to identify protein interactions for JQ1, single ubiquitin peptide, and NS5 protein of Zika virus. From PLATO-BC analyses, we identified new protein interactions for these "bait" molecules. We demonstrate that Ewing sarcoma breakpoint region 1 (EWSR1) binds to JQ1 and their interactions may interrupt the EWSR1 association with acetylated histone H4. RIO kinase 3 (RIOK3), a newly identified ubiquitin-binding protein, is preferentially associated with K63-ubiquitin chain. We also find that Zika NS5 protein interacts with two previously unreported host proteins, par-3 family cell polarity regulator (PARD3) and chromosome 19 open reading frame 53 (C19orf53), whose attenuated expression benefits the replication of Zika virus. These results further demonstrate that PLATO-BC is capable of identifying novel protein interactions for various types of "bait" molecules.

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Proteomics Analysis of Lipid Droplets from the Oleaginous Alga Chromochloris zofingiensis Reveals Novel Proteins for Lipid Metabolism.

Xiaofei WANG ; Hehong WEI ; Xuemei MAO ; Jin LIU

Genomics, Proteomics & Bioinformatics.2019;17(3):260-272. doi:10.1016/j.gpb.2019.01.003

Chromochloris zofingiensis represents an industrially relevant and unique green alga, given its capability of synthesizing triacylglycerol (TAG) and astaxanthin simultaneously for storage in lipid droplets (LDs). To further decipher lipid metabolism, the nitrogen deprivation (ND)-induced LDs from C. zofingiensis were isolated, purified, and subjected to proteomic analysis. Intriguingly, many C. zofingiensis LD proteins had no orthologs present in LD proteome of the model alga Chlamydomonas reinhardtii. Seven novel LD proteins (i.e., two functionally unknown proteins, two caleosins, two lipases, and one l-gulonolactone oxidase) and the major LD protein (MLDP), which were all transcriptionally up-regulated by ND, were selected for further investigation. Heterologous expression in yeast demonstrated that all tested LD proteins were localized to LDs and all except the two functionally unknown proteins enabled yeast to produce more TAG. MLDP could restore the phenotype of mldp mutant strain and enhance TAG synthesis in wild-type strain of C. reinhardtii. Although MLDP and caleosins had a comparable abundance in LDs, they responded distinctly to ND at the transcriptional level. The two lipases, instead of functioning as TAG lipases, likely recycled polar lipids to support TAG synthesis. For the first time, we reported that l-gulonolactone oxidase was abundant in LDs and facilitated TAG accumulation. Moreover, we also proposed a novel working model for C. zofingiensis LDs. Taken together, our work unravels the unique characteristics of C. zofingiensis LDs and provides insights into algal LD biogenesis and TAG synthesis, which would facilitate genetic engineering of this alga for TAG improvement.

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