The Implications of ncRNAs in the Development of Human Diseases

The mammalian genome comprehends a small minority of genes that encode for proteins (barely 2% of the total genome in humans) and an immense majority of genes that are transcribed into RNA but not encoded for proteins (ncRNAs). These non-coding genes are intimately related to the expression regulation of protein-coding genes. The ncRNAs subtypes differ in their size, so there are long non-coding genes (lncRNAs) and other smaller ones, like microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs). Due to their important role in the maintenance of cellular functioning, any deregulation of the expression profiles of these ncRNAs can dissemble in the development of different types of diseases. Among them, we can highlight some of high incidence in the population, such as cancer, neurodegenerative, or cardiovascular disorders. In addition, thanks to the enormous advances in the field of medical genomics, these same ncRNAs are starting to be used as possible drugs, approved by the FDA, as an effective treatment for diseases.

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Overlapping protein-coding genes in human genome and their coincidental expression in tissues

Scientific Reports ◽

10.1038/s41598-019-49802-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Chao-Hsin Chen ◽

Chao-Yu Pan ◽

Wen-chang Lin

Keyword(s):

Human Genome ◽

Expression Profiles ◽

Tissue Expression ◽

Human Protein ◽

Clear Understanding ◽

Overlapping Genes ◽

Genome Sequences ◽

Protein Coding ◽

Protein Coding Genes ◽

Overlapping Gene

Abstract The completion of human genome sequences and the advancement of next-generation sequencing technologies have engendered a clear understanding of all human genes. Overlapping genes are usually observed in compact genomes, such as those of bacteria and viruses. Notably, overlapping protein-coding genes do exist in human genome sequences. Accordingly, we used the current Ensembl gene annotations to identify overlapping human protein-coding genes. We analysed 19,200 well-annotated protein-coding genes and determined that 4,951 protein-coding genes overlapped with their adjacent genes. Approximately a quarter of all human protein-coding genes were overlapping genes. We observed different clusters of overlapping protein-coding genes, ranging from two genes (paired overlapping genes) to 22 genes. We also divided the paired overlapping protein-coding gene groups into four subtypes. We found that the divergent overlapping gene subtype had a stronger expression association than did the subtypes of 5ʹ-tandem overlapping and 3ʹ-tandem overlapping genes. The majority of paired overlapping genes exhibited comparable coincidental tissue expression profiles; however, a few overlapping gene pairs displayed distinctive tissue expression association patterns. In summary, we have carefully examined the genomic features and distributions about human overlapping protein-coding genes and found coincidental expression in tissues for most overlapping protein-coding genes.

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LncExpDB: an expression database of human long non-coding RNAs

Nucleic Acids Research ◽

10.1093/nar/gkaa850 ◽

2020 ◽

Vol 49 (D1) ◽

pp. D962-D968 ◽

Cited By ~ 2

Author(s):

Zhao Li ◽

Lin Liu ◽

Shuai Jiang ◽

Qianpeng Li ◽

Changrui Feng ◽

...

Keyword(s):

Expression Profiles ◽

Biological Functions ◽

Protein Coding ◽

Web Interfaces ◽

Functional Studies ◽

Protein Coding Genes ◽

Genes Expression ◽

Wide Range ◽

Non Coding Rnas ◽

User Friendly

Abstract Expression profiles of long non-coding RNAs (lncRNAs) across diverse biological conditions provide significant insights into their biological functions, interacting targets as well as transcriptional reliability. However, there lacks a comprehensive resource that systematically characterizes the expression landscape of human lncRNAs by integrating their expression profiles across a wide range of biological conditions. Here, we present LncExpDB (https://bigd.big.ac.cn/lncexpdb), an expression database of human lncRNAs that is devoted to providing comprehensive expression profiles of lncRNA genes, exploring their expression features and capacities, identifying featured genes with potentially important functions, and building interactions with protein-coding genes across various biological contexts/conditions. Based on comprehensive integration and stringent curation, LncExpDB currently houses expression profiles of 101 293 high-quality human lncRNA genes derived from 1977 samples of 337 biological conditions across nine biological contexts. Consequently, LncExpDB estimates lncRNA genes’ expression reliability and capacities, identifies 25 191 featured genes, and further obtains 28 443 865 lncRNA-mRNA interactions. Moreover, user-friendly web interfaces enable interactive visualization of expression profiles across various conditions and easy exploration of featured lncRNAs and their interacting partners in specific contexts. Collectively, LncExpDB features comprehensive integration and curation of lncRNA expression profiles and thus will serve as a fundamental resource for functional studies on human lncRNAs.

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Human CHR18: “Stakhanovite” Genes, Missing and uPE1 Proteins in Liver Tissue and HepG2 Cells

Biomedical Chemistry Research and Methods ◽

10.18097/bmcrm00144 ◽

2021 ◽

Vol 4 (1) ◽

pp. e00144

Author(s):

K.A. Deinichenko ◽

G.S. Krasnov ◽

S.P. Radko ◽

K.G. Ptitsyn ◽

V.V. Shapovalova ◽

...

Keyword(s):

Gene Expression ◽

Correlation Analysis ◽

Quantitative Pcr ◽

Liver Tissue ◽

Hepg2 Cells ◽

Expression Profiles ◽

Normal Liver ◽

Illumina Hiseq ◽

Protein Coding ◽

Protein Coding Genes

Missing (MP) and functionally uncharacterized proteins (uPE1) comprise less than 5% of the total number of proteins encoded by human Chr18 genes. Within half a year, since the January 2020 version of NextProt, the number of entries in the MP+uPE1 datasets changed, mainly due to the achievements of antibody-based proteomics. Assuming that the proteome is closely related to the transcriptome scaffold, quantitative PCR, Illumina HiSeq, and Oxford Nanopore Technology were applied to characterize the liver samples of three male donors in comparison with the HepG2 cell line. The data mining of the Expression Atlas (EMBL-EBI) and the profiling of biopsy samples by using orthogonal methods of transcriptome analysis have shown that in HepG2 cells and the liver, the genes encoding functionally uncharacterized proteins (uPE1) are expressed as low as for the missing proteins (less than 1 copy per cell), except the selected cases of HSBP1L1, TMEM241, C18orf21, and KLHL14. The initial expectation that uPE1 genes might be expressed at higher levels than MP genes, was compromised by severe discrepancies in our semi-quantitative gene expression data and in public databanks. Such discrepancy forced us to revisit the transcriptome of Chr18, the target of the Russian C-HPP Consortium. Tanglegram of highly expressed genes and further correlation analysis have shown the severe dependencies on the mRNA extraction method and the analytical platform. Targeted gene expression analysis by quantitative PCR (qPCR) and high-throughput transcriptome profiling (Illumina HiSeq and ONT MinION) for the same set of samples from normal liver tissue and HepG2 cells revealed the detectable expression of 250+ (92%) protein-coding genes of Chr18 (at least one method). The expression of slightly more than 50% protein-coding genes was detected simultaneously by all three methods. Correlation analysis of the gene expression profiles showed that the grouping of the datasets depended almost equally on both the type of biological material and the experimental method, particularly cDNA/mRNA isolation and library preparation.

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Genome-wide identification and comparison of differentially expressed profiles of miRNAs and lncRNAs with associated ceRNA networks in the gonads of Chinese soft-shelled turtle, Pelodiscus sinensis

10.21203/rs.2.10525/v4 ◽

2020 ◽

Author(s):

Xiao Ma ◽

Shuangshuang Cen ◽

Luming Wang ◽

Chao Zhang ◽

Limin Wu ◽

...

Keyword(s):

Messenger Rna ◽

Target Genes ◽

Expression Profiles ◽

Differentially Expressed ◽

Integrated Analysis ◽

Pelodiscus Sinensis ◽

Specific Expression ◽

Protein Coding ◽

Reproductive Regulation ◽

Protein Coding Genes

Abstract Background: The gonad is the major factor affecting animal reproduction. The regulatory mechanism of the expression of protein-coding genes involved in reproduction still remains to be elucidated. Increasing evidence has shown that ncRNAs play key regulatory roles in gene expression in many life processes. The roles of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in reproduction have been investigated in some species. However, the regulatory patterns of miRNA and lncRNA in the sex biased expression of protein coding genes remains to be elucidated. In this study, we performed an integrated analysis of miRNA, messenger RNA (mRNA), and lncRNA expression profiles to explore their regulatory patterns in the female ovary and male testis of Chinese soft-shelled turtle, Pelodiscus sinensis.Results: We identified 10 446 mature miRNAs, 20 414 mRNAs and 28 500 lncRNAs in the ovaries and testes, and 633 miRNAs, 11 319 mRNAs, and 10 495 lncRNAs showed differential expression. A total of 2 814 target genes were identified for miRNAs. The predicted target genes of these differentially expressed (DE) miRNAs and lncRNAs included abundant genes related to reproductive regulation. Furthermore, we found that 189 DEmiRNAs and 5 408 DElncRNAs showed sex-specific expression. Of these, 3 DEmiRNAs and 917 DElncRNAs were testis-specific, and 186 DEmiRNAs and 4 491 DElncRNAs were ovary-specific. We further constructed complete endogenous lncRNA-miRNA-mRNA networks using bioinformatics, including 103 DEmiRNAs, 636 DEmRNAs, and 1 622 DElncRNAs. The target genes for the differentially expressed miRNAs and lncRNAs included abundant genes involved in gonadal development, including Wt1, Creb3l2, Gata4, Wnt2, Nr5a1, Hsd17, Igf2r, H2afz, Lin52, Trim71, Zar1, and Jazf1.Conclusions: In animals, miRNA and lncRNA as master regulators regulate reproductive processes by controlling the expression of mRNAs. Considering their importance, the identified miRNAs, lncRNAs, and their targets in P. sinensis might be useful for studying the molecular processes involved in sexual reproduction and genome editing to produce higher quality aquaculture animals. A thorough understanding of ncRNA-based cellular regulatory networks will aid in the improvement of P. sinensis reproductive traits for aquaculture.

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Genome-wide identification and comparison of differentially expressed profiles of miRNAs and lncRNAs with associated ceRNA networks in the gonads of Chinese soft-shelled turtle, Pelodiscus sinensis

10.21203/rs.2.10525/v1 ◽

2019 ◽

Author(s):

Xiao Ma ◽

Shuangshuang Cen ◽

Luming Wang ◽

Chao Zhang ◽

Limin Wu ◽

...

Keyword(s):

Messenger Rna ◽

Regulatory Networks ◽

Target Genes ◽

Expression Profiles ◽

Integrated Analysis ◽

Regulation Mechanism ◽

Pelodiscus Sinensis ◽

Specific Expression ◽

Protein Coding ◽

Protein Coding Genes

Abstract Abstract Background: Gonad is the major factor affecting the animal reproduction. The regulation mechanism of protein coding genes expression involved reproduction is still remains to be elucidated. Increasing evidence has shown that ncRNAs play key regulatory roles in gene expression in many life processes. The roles of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in reproduction had been investigated in some species. However, the regulation patterns of miRNA and lncRNA in sex biased expression of protein coding genes remains to be elucidated. In this study, we performed an integrated analysis of miRNA, messenger RNA (mRNA), and lncRNA expression profiles to explore their regulatory patterns in the female ovary and male testis of the soft-shelled turtle, Pelodiscus sinensis. Results: We identified 10 796 mature miRNAs, 44 678 mRNAs, and 58 923 lncRNAs in the testis and ovary. A total of 16 817 target genes were identified for miRNAs. Of these, 11 319 mRNAs, 10 495 lncRNAs, and 633 miRNAs were expressed differently. The predicted target genes of these differential expression (DE) miRNAs and lncRNAs included genes related to reproduction regulation. Furthermore, we found that 5 408 DElncRNAs and 186 DE miRNAs showed sex-specific expression. Of these, 3 miRNAs and 917 lncRNAs were testis specific and 186 DEmiRNAs and 4 491 DElncRNAs were ovary specific. We constructed compete endogenous lncRNA-miRNA-mRNA networks using bioinformatics, including 273 DEmRNAs, 5 730 DEmiRNAs, and 2 945 DElncRNAs. The target genes for the different expressed of miRNAs and lncRNAs included Wt1, Creb3l2, Gata4, Wnt2, Nr5a1, Hsd17, Igf2r, H2afz, Lin52, Trim71, Zar1, and Jazf1, etc. Conclusions: In animals, miRNA and lncRNA regulate the reproduction process, including the regulation of oocyte maturation and spermatogenesis. Considering their importance, the identified miRNAs, lncRNAs, and their targets in P. sinensis might be useful for genome editing to produce higher quality aquaculture animals. A thorough understanding of ncRNA-based cellular regulatory networks will aid in the improvement of P. sinensis reproduction traits for aquaculture.

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Evolutionary Rate Heterogeneity and Functional Divergence of Orthologous Genes in Pyrus

Biomolecules ◽

10.3390/biom9090490 ◽

2019 ◽

Vol 9 (9) ◽

pp. 490 ◽

Cited By ~ 2

Author(s):

Yunpeng Cao ◽

Lan Jiang ◽

Lihu Wang ◽

Yongping Cai

Keyword(s):

Expression Profiles ◽

Functional Divergence ◽

Expression Patterns ◽

Synonymous Substitution ◽

Evolutionary Rates ◽

Orthologous Genes ◽

Protein Coding ◽

Different Types ◽

Synonymous Substitution Rates ◽

Gene Structures

Negatively selected genes (NSGs) and positively selected genes (PSGs) are the two types of most nuclear protein-coding genes in organisms. However, the evolutionary rates and characteristics of different types of genes have been rarely understood. In the present study, we investigate the rates of synonymous substitution (Ks) and the rates of non-synonymous substitution (Ka) by comparing the orthologous genes of two sequenced Pyrus species, Pyrus bretschneideri and Pyrus communis. Subsequently, we compared the evolutionary rates, gene structures, and expression profiles during different fruit development between PSGs and NSGs. Compared with the NSGs, the PSGs have fewer exons, shorter gene length, lower synonymous substitution rates and have higher evolutionary rates. Remarkably, gene expression patterns between two Pyrus species fruit indicated functional divergence for most of the orthologous genes derived from a common ancestor, and subfunctionalization for some of them. Overall, the present study shows that PSGs differs from NSGs not only under environmental selective pressure (Ka/Ks), but also in their structural, functional, and evolutionary properties. Additionally, our resulting data provides important insights for the evolution and highlights the diversification of orthologous genes in two Pyrus species.

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Mammary Epithelial Cell Transcriptome Reveals Potential Roles of lncRNAs in Regulating Milk Synthesis Pathways in Jersey and Kashmiri Cattle

10.21203/rs.3.rs-281012/v1 ◽

2021 ◽

Author(s):

Peerzada Tajamul Mumtaz ◽

Basharat Bhat ◽

Eveline M. Ibeagha-Awemu ◽

Qamar Taban ◽

Mengqi Wang ◽

...

Keyword(s):

Mammary Gland ◽

Mammary Gland Development ◽

Expression Profiles ◽

Regulatory Elements ◽

Milk Quality ◽

Mammary Epithelial ◽

Protein Coding ◽

Protein Coding Genes ◽

Gland Development

Abstract Background Long noncoding RNAs (lncRNAs) are now proven as essential regulatory elements, playing diverse role in many biological processes including mammary gland development. However, little is known about their roles in bovine lactation process. There are very few reports available to date on the role of lncRNAs in lactation physiology and mammary glands development in cattle. Results To identify and characterize the roles of lncRNAs in bovine lactation, milk derived mammary epithelial cells (MEC) from Jersey (high milk producer) and Kashmiri cattle (low milk producer) at early, mid and late lactation stages were used. The lncRNA transcriptome of the samples (n=18) was studied using next generation RNA sequencing technology. 633 putative lncRNAs were identified, 76 of which were differentially expressed (DE) between comparison between the three stages of lactation. Additionally, 56 DE lncRNAs were identified from 9 Jersey and 9 Kashmir samples. Correlation of DE lncRNAs with protein-coding genes resulted in a comprehensive list of lncRNA-mRNA co-expressed pairs. Most of the DE lncRNAs showed positive correlations with protein coding genes in Jersey compared to Kashmiri cattle where they were mainly negatively correlated, which could be one of the underlying mechanisms responsible for the differential milking performance between the two breeds. In addition, a number of the DE lncRNAs were paired with the most DE milk quality genes like GPAM, LPL, ABCG2, etc. indicative of their potential regulatory effects on milk quality genes. KEGG pathways analysis of potential cis and trans target genes of DE lncRNAs indicated that 27 and 48 pathways were significantly enriched in Kashmiri and Jersey respectively, including mTOR signaling, PI3K-Akt signaling and RAP1 signaling pathways. These pathways have been proven to play key roles in lactation biology and mammary gland development. Conclusions Our study mapped the expression profiles of lncRNAs across lactation stages and their relationships with candidate genes related to milk quality and yield traits in Jersey and Kashmiri cattle. These findings provide a valuable resource for the study of the regulatory mechanisms involved in the lactation process as well as facilitate understanding of the role of lncRNAs in bovine lactation biology.

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Beyond mRNAs and Mirnas: Unraveling the Full-Spectrum of the Normal Human Platelet Transcriptome Through Next-Generation Sequencing

Blood ◽

10.1182/blood.v120.21.3298.3298 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3298-3298 ◽

Cited By ~ 2

Author(s):

Eric R. Londin ◽

Eleftheria Hatzimichael ◽

Phillipe Loher ◽

Yue Zhao ◽

Yi Jing ◽

...

Keyword(s):

Molecular Mechanisms ◽

Conflicts Of Interest ◽

Expression Profiles ◽

Pearson Correlation ◽

Critical Role ◽

Ltr Retrotransposons ◽

Rna Seq ◽

Ensembl Database ◽

Protein Coding ◽

Protein Coding Genes

Abstract Abstract 3298 The anucleate platelets play a critical role in the formation of thrombi and prevention of bleeding. While the repertoire of platelet transcripts is a reflection of the megakaryocyte at the time of platelet differentiation, post-transcriptional events are known to occur. Furthermore, a strong correlation between the expressed mRNAs and proteome has been identified. Having a complete understanding of the platelet transcriptome is important for generating insights into the genetic basis of platelet disease traits. To capture the complexity of the platelet transcriptome, we performed RNA sequencing (RNA-seq) in leukocyte-depleted platelets from 10 males, with median age of 24.5 yrs and unremarkable medical history. Their short and long RNA platelet transcriptomes were analyzed on the SOLiD 5500xl sequencing platform. We generated ∼3.5 billion sequence reads ∼40% of which could be mapped uniquely to the human genome. Our analysis revealed that ∼9,000 distinct protein-coding mRNAs and ∼800 microRNAs (miRNAs) were present in the transcriptome of each of the 10 sequenced individuals. Comparison of the levels of mRNA expression across the 10 individuals showed an exceptional level of consistency with pair-wise Pearson correlation values ≥0.98. The miRNA expression profiles across the 10 individuals showed a similar consistency with pair-wise Pearson correlation values ≥0.98. Surprisingly, we found that these mRNAs and miRNAs accounted for a little over 1/2 of all of the uniquely mapped sequence reads suggesting the abundant presence of additional non-protein coding RNA (ncRNA) transcripts. Using the annotated entries of the latest release of the ENSEMBL database, we investigated the genetic make-up of these other transcripts. We found that ∼25% of each individual's uniquely mapped reads corresponded to non-protein coding transcripts from mRNA-coding loci. These reads accounted for more than 10,000 distinct such transcripts. In addition, each of the individuals in our cohort expressed an average of ∼1,500 pseudogenes and ∼200 long intergenic non-coding RNAs (lincRNAs). The short RNA profiles of the ten individuals revealed an abundance of diverse categories of ncRNAs including the signal recognition particle RNA (srpRNA), small nuclear RNA (snRNA) and small cytoplasmic RNAs (scRNA). These ncRNAs are involved in the processing of pre-mRNAs and their presence and prevalence in the anucleate platetet suggests the existence of a complex network of mRNA processing that persists after the megakaryocyte fragmentation. We also investigated the RNA-omes of the ten individuals for evidence of transcription of the pyknon category of ncRNAs. Pyknons are of particular interest because each has numerous intergenic and intronic copies whereas nearly all known human protein-coding genes contain one or more pyknons in their mRNA. Recent experimental work has shown that intergenic instances of the pyknons are transcribed in a tissue- and cell-state specific manner. An average of ∼100,000 pyknons are transcribed in each of the 10 sequenced individuals suggesting the possibility of a far-reaching network of interactions that link exonic space to distant non-exonic regions and are active in platelets. Lastly, we found that a large variety of distinct repeat element categories are expressed in the RNA-omes (both short and long) of these individuals. Among the most abundantly represented categories of repeat elements were DNA transposons, long terminal repeat (LTR) retrotransposons, and non-LTR retrotransposons such as long interspersed elements (LINEs) and short interspersed elements (SINEs). In summary, our RNA-seq analyses have revealed a spectrum of platelet transcripts that transcends protein-coding genes and miRNAs. Indeed, the transcripts that have their source in genomic features not previously discussed or analyzed in the platelet context represent a very significant portion of all platelet transcripts. This in turn suggests an unanticipated richness, and presumably commensurate complexity, for the platelet transcriptome. While the role of these novel non-protein coding RNAs is currently unknown it is expected that at least some of them may be of functional significance which will in turn permit a better understanding of the molecular mechanisms that regulate platelet physiology and may contribute to processes beyond thrombosis and hemostasis. Disclosures: No relevant conflicts of interest to declare.

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Systematic analyses reveal long non-coding RNA (PTAF)-mediated promotion of EMT and invasion-metastasis in serous ovarian cancer

Molecular Cancer ◽

10.1186/s12943-018-0844-7 ◽

2018 ◽

Vol 17 (1) ◽

Cited By ~ 20

Author(s):

Haihai Liang ◽

Xiaoguang Zhao ◽

Chengyu Wang ◽

Jian Sun ◽

Yingzhun Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Expression Profiles ◽

In Vivo Studies ◽

Clinical Samples ◽

Orthotopic Mouse Model ◽

Protein Coding ◽

Mesenchymal Transition ◽

Protein Coding Genes

Abstract Background A deeper mechanistic understanding of epithelial-to-mesenchymal transition (EMT) regulation is needed to improve current anti-metastasis strategies in ovarian cancer (OvCa). This study was designed to investigate the role of lncRNAs in EMT regulation during process of invasion-metastasis in serous OvCa to improve current anti-metastasis strategies for OvCa. Methods We systematically analyzes high-throughput gene expression profiles of both lncRNAs and protein-coding genes in OvCa samples with integrated epithelial (iE) subtype and integrated mesenchymal (iM) subtype labels. Mouse models, cytobiology, molecular biology assays and clinical samples were performed to elucidate the function and underlying mechanisms of lncRNA PTAF-mediated promotion of EMT and invasion-metastasis in serous OvCa. Results We constructed a lncRNA-mediated competing endogenous RNA (ceRNA) regulatory network that affects the expression of many EMT-related protein-coding genes in mesenchymal OvCa. Using a combination of in vitro and in vivo studies, we provided evidence that the lncRNA PTAF-miR-25-SNAI2 axis controlled EMT in OvCa. Our results revealed that up-regulated PTAF induced elevated SNAI2 expression by competitively binding to miR-25, which in turn promoted OvCa cell EMT and invasion. Moreover, we found that silencing of PTAF inhibited tumor progression and metastasis in an orthotopic mouse model of OvCa. We then observed a significant correlation between PTAF expression and EMT markers in OvCa patients. Conclusions The lncRNA PTAF, a mediator of TGF-β signaling, can predispose OvCa patients to metastases and may serve as a potential target for anti-metastatic therapies for mesenchymal OvCa patients.

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