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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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Transcriptome-wide Dynamics of m⁶A mRNA Methylation During Porcine Spermatogenesis.

Zidong LIU ; Xiaoxu CHEN ; Pengfei ZHANG ; Fuyuan LI ; Lingkai ZHANG ; Xueliang LI ; Tao HUANG ; Yi ZHENG ; Taiyong YU ; Tao ZHANG ; Wenxian ZENG ; Hongzhao LU ; Yinghua LV

Genomics, Proteomics & Bioinformatics.2023;21(4):729-741. doi:10.1016/j.gpb.2021.08.006

Spermatogenesis is a continual process that occurs in the testes, in which diploid spermatogonial stem cells (SSCs) differentiate and generate haploid spermatozoa. This highly efficient and intricate process is orchestrated at multiple levels. N⁶-methyladenosine (m⁶A), an epigenetic modification prevalent in mRNAs, is implicated in the transcriptional regulation during spermatogenesis. However, the dynamics of m⁶A modification in non-rodent mammalian species remains unclear. Here, we systematically investigated the profile and role of m⁶A during spermatogenesis in pigs. By analyzing the transcriptomic distribution of m⁶A in spermatogonia, spermatocytes, and round spermatids, we identified a globally conserved m⁶A pattern between porcine and murine genes with spermatogenic function. We found that m⁶A was enriched in a group of genes that specifically encode the metabolic enzymes and regulators. In addition, transcriptomes in porcine male germ cells could be subjected to the m⁶A modification. Our data show that m⁶A plays the regulatory roles during spermatogenesis in pigs, which is similar to that in mice. Illustrations of this point are three genes (SETDB1, FOXO1, and FOXO3) that are crucial to the determination of the fate of SSCs. To the best of our knowledge, this study for the first time uncovers the expression profile and role of m⁶A during spermatogenesis in large animals and provides insights into the intricate transcriptional regulation underlying the lifelong male fertility in non-rodent mammalian species.
Animals ; Male ; Mice ; Cell Differentiation/genetics* ; Mammals/metabolism* ; Methylation ; RNA, Messenger/metabolism* ; Spermatogenesis/genetics* ; Spermatozoa/metabolism* ; Swine/genetics* ; Testis/metabolism* ; Transcriptome ; RNA Methylation/genetics*

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Specific Regulation of m⁶A by SRSF7 Promotes the Progression of Glioblastoma.

Yixian CUN ; Sanqi AN ; Haiqing ZHENG ; Jing LAN ; Wenfang CHEN ; Wanjun LUO ; Chengguo YAO ; Xincheng LI ; Xiang HUANG ; Xiang SUN ; Zehong WU ; Yameng HU ; Ziwen LI ; Shuxia ZHANG ; Geyan WU ; Meisongzhu YANG ; Miaoling TANG ; Ruyuan YU ; Xinyi LIAO ; Guicheng GAO ; Wei ZHAO ; Jinkai WANG ; Jun LI

Genomics, Proteomics & Bioinformatics.2023;21(4):707-728. doi:10.1016/j.gpb.2021.11.001

Serine/arginine-rich splicing factor 7 (SRSF7), a known splicing factor, has been revealed to play oncogenic roles in multiple cancers. However, the mechanisms underlying its oncogenic roles have not been well addressed. Here, based on N⁶-methyladenosine (m⁶A) co-methylation network analysis across diverse cell lines, we find that the gene expression of SRSF7 is positively correlated with glioblastoma (GBM) cell-specific m⁶A methylation. We then indicate that SRSF7 is a novel m⁶A regulator, which specifically facilitates the m⁶A methylation near its binding sites on the mRNAs involved in cell proliferation and migration, through recruiting the methyltransferase complex. Moreover, SRSF7 promotes the proliferation and migration of GBM cells largely dependent on the presence of the m⁶A methyltransferase. The two m⁶A sites on the mRNA for PDZ-binding kinase (PBK) are regulated by SRSF7 and partially mediate the effects of SRSF7 in GBM cells through recognition by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Together, our discovery reveals a novel role of SRSF7 in regulating m⁶A and validates the presence and functional importance of temporal- and spatial-specific regulation of m⁶A mediated by RNA-binding proteins (RBPs).
Humans ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Glioblastoma/genetics* ; Methyltransferases/metabolism* ; RNA Splicing Factors/metabolism* ; RNA, Messenger/genetics* ; RNA-Binding Proteins/metabolism* ; Serine-Arginine Splicing Factors/metabolism* ; RNA Methylation/genetics*

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Screening Linear and Circular RNA Transcripts from Stress Granules.

Shuai CHEN ; Jinyang ZHANG ; Fangqing ZHAO

Genomics, Proteomics & Bioinformatics.2023;21(4):886-893. doi:10.1016/j.gpb.2022.01.003

Stress granules (SGs) are cytoplasmic ribonucleoprotein assemblies formed under stress conditions and are related to various biological processes and human diseases. Previous studies have reported the regulatory role of some proteins and linear RNAs in SG assembly. However, the relationship between circular RNAs (circRNAs) and SGs has not been discovered. Here, we screened both linear RNAs and circRNAs in SGs using improved total RNA sequencing of purified SG cores in mammalian cells and identified circular transcripts specifically localized in SGs. circRNAs with higher SG-related RNA-binding protein (RBP) binding abilities are more likely to be enriched in SGs. Furthermore, some SG-enriched circRNAs are differentially expressed in hepatocellular carcinoma (HCC) and adjacent tissues. These results suggest the regulatory role of circRNAs in SG formation and provide insights into the biological function of circRNAs and SGs in HCC.
Animals ; Humans ; RNA, Circular/metabolism* ; Carcinoma, Hepatocellular/metabolism* ; Stress Granules ; Cytoplasmic Granules/metabolism* ; Liver Neoplasms/metabolism* ; RNA/metabolism* ; Stress, Physiological/genetics* ; Mammals/genetics*

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Characteristics of N⁶-methyladenosine Modification During Sexual Reproduction of Chlamydomonas reinhardtii.

Ying LV ; Fei HAN ; Mengxia LIU ; Ting ZHANG ; Guanshen CUI ; Jiaojiao WANG ; Ying YANG ; Yun-Gui YANG ; Wenqiang YANG

Genomics, Proteomics & Bioinformatics.2023;21(4):756-768. doi:10.1016/j.gpb.2022.04.004

The unicellular green alga Chlamydomonas reinhardtii (hereafter Chlamydomonas) possesses both plant and animal attributes, and it is an ideal model organism for studying fundamental processes such as photosynthesis, sexual reproduction, and life cycle. N⁶-methyladenosine (m⁶A) is the most prevalent mRNA modification, and it plays important roles during sexual reproduction in animals and plants. However, the pattern and function of m⁶A modification during the sexual reproduction of Chlamydomonas remain unknown. Here, we performed transcriptome and methylated RNA immunoprecipitation sequencing (MeRIP-seq) analyses on six samples from different stages during sexual reproduction of the Chlamydomonas life cycle. The results show that m⁶A modification frequently occurs at the main motif of DRAC (D = G/A/U, R = A/G) in Chlamydomonas mRNAs. Moreover, m⁶A peaks in Chlamydomonas mRNAs are mainly enriched in the 3' untranslated regions (3'UTRs) and negatively correlated with the abundance of transcripts at each stage. In particular, there is a significant negative correlation between the expression levels and the m⁶A levels of genes involved in the microtubule-associated pathway, indicating that m⁶A modification influences the sexual reproduction and the life cycle of Chlamydomonas by regulating microtubule-based movement. In summary, our findings are the first to demonstrate the distribution and the functions of m⁶A modification in Chlamydomonas mRNAs and provide new evolutionary insights into m⁶A modification in the process of sexual reproduction in other plant organisms.
Animals ; Chlamydomonas reinhardtii/metabolism* ; Reproduction/genetics* ; Life Cycle Stages/genetics* ; Transcriptome ; Plants/genetics*

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