Publications by authors named "David L Adelson"

75 Publications

Horizontal transfer and subsequent explosive expansion of a DNA transposon in sea kraits ().

Biol Lett 2021 09 1;17(9):20210342. Epub 2021 Sep 1.

School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia.

Transposable elements (TEs) are self-replicating genetic sequences and are often described as important 'drivers of evolution'. This driving force is because TEs promote genomic novelty by enabling rearrangement, and through exaptation as coding and regulatory elements. However, most TE insertions potentially lead to neutral or harmful outcomes, therefore host genomes have evolved machinery to suppress TE expansion. Through horizontal transposon transfer (HTT) TEs can colonize new genomes, and since new hosts may not be able to regulate subsequent replication, these TEs may proliferate rapidly. Here, we describe HTT of the DNA transposon into sea kraits (), and its subsequent explosive expansion within genomes. This HTT occurred following the divergence of from terrestrial Australian elapids approximately 15-25 Mya. This has resulted in numerous insertions into introns and regulatory regions, with some insertions into exons which appear to have altered UTRs or added sequence to coding exons. has rapidly expanded to make up 8-12% of spp. genomes; this is the fastest known expansion of TEs in amniotes following HTT. Genomic changes caused by this rapid expansion may have contributed to adaptation to the amphibious-marine habitat.
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http://dx.doi.org/10.1098/rsbl.2021.0342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437027PMC
September 2021

The long noncoding RNA FRILAIR regulates strawberry fruit ripening by functioning as a noncanonical target mimic.

PLoS Genet 2021 03 19;17(3):e1009461. Epub 2021 Mar 19.

Key Laboratory of Molecular Biology and Gene Engineering in Jiangxi Province, College of Life Science, Nanchang University, Nanchang, China.

Long noncoding RNAs (lncRNAs) are emerging as important regulators in plant development, but few of them have been functionally characterized in fruit ripening. Here, we have identified 25,613 lncRNAs from strawberry ripening fruits based on RNA-seq data from poly(A)-depleted libraries and rRNA-depleted libraries, most of which exhibited distinct temporal expression patterns. A novel lncRNA, FRILAIR harbours the miR397 binding site that is highly conserved in diverse strawberry species. FRILAIR overexpression promoted fruit maturation in the Falandi strawberry, which was consistent with the finding from knocking down miR397, which can guide the mRNA cleavage of both FRILAIR and LAC11a (encoding a putative laccase-11-like protein). Moreover, LAC11a mRNA levels were increased in both FRILAIR overexpressing and miR397 knockdown fruits, and accelerated fruit maturation was also found in LAC11a overexpressing fruits. Overall, our study demonstrates that FRILAIR can act as a noncanonical target mimic of miR397 to modulate the expression of LAC11a in the strawberry fruit ripening process.
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http://dx.doi.org/10.1371/journal.pgen.1009461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011760PMC
March 2021

New Environment, New Invaders-Repeated Horizontal Transfer of LINEs to Sea Snakes.

Genome Biol Evol 2020 12;12(12):2370-2383

School of Biological Sciences, University of Adelaide, Australia.

Although numerous studies have found horizontal transposon transfer (HTT) to be widespread across metazoans, few have focused on HTT in marine ecosystems. To investigate potential recent HTTs into marine species, we searched for novel repetitive elements in sea snakes, a group of elapids which transitioned to a marine habitat at most 18 Ma. Our analysis uncovered repeated HTTs into sea snakes following their marine transition. The seven subfamilies of horizontally transferred LINE retrotransposons we identified in the olive sea snake (Aipysurus laevis) are transcribed, and hence are likely still active and expanding across the genome. A search of 600 metazoan genomes found all seven were absent from other amniotes, including terrestrial elapids, with the most similar LINEs present in fish and marine invertebrates. The one exception was a similar LINE found in sea kraits, a lineage of amphibious elapids which independently transitioned to a marine environment 25 Ma. Our finding of repeated horizontal transfer events into marine snakes greatly expands past findings that the marine environment promotes the transfer of transposons. Transposons are drivers of evolution as sources of genomic sequence and hence genomic novelty. We identified 13 candidate genes for HTT-induced adaptive change based on internal or neighboring HTT LINE insertions. One of these, ADCY4, is of particular interest as a part of the KEGG adaptation pathway "Circadian Entrainment." This provides evidence of the ecological interactions between species influencing evolution of metazoans not only through specific selection pressures, but also by contributing novel genomic material.
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http://dx.doi.org/10.1093/gbe/evaa208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846101PMC
December 2020

The tuatara genome reveals ancient features of amniote evolution.

Nature 2020 08 5;584(7821):403-409. Epub 2020 Aug 5.

Department of Anatomy, University of Otago, Dunedin, New Zealand.

The tuatara (Sphenodon punctatus)-the only living member of the reptilian order Rhynchocephalia (Sphenodontia), once widespread across Gondwana-is an iconic species that is endemic to New Zealand. A key link to the now-extinct stem reptiles (from which dinosaurs, modern reptiles, birds and mammals evolved), the tuatara provides key insights into the ancestral amniotes. Here we analyse the genome of the tuatara, which-at approximately 5 Gb-is among the largest of the vertebrate genomes yet assembled. Our analyses of this genome, along with comparisons with other vertebrate genomes, reinforce the uniqueness of the tuatara. Phylogenetic analyses indicate that the tuatara lineage diverged from that of snakes and lizards around 250 million years ago. This lineage also shows moderate rates of molecular evolution, with instances of punctuated evolution. Our genome sequence analysis identifies expansions of proteins, non-protein-coding RNA families and repeat elements, the latter of which show an amalgam of reptilian and mammalian features. The sequencing of the tuatara genome provides a valuable resource for deep comparative analyses of tetrapods, as well as for tuatara biology and conservation. Our study also provides important insights into both the technical challenges and the cultural obligations that are associated with genome sequencing.
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http://dx.doi.org/10.1038/s41586-020-2561-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116210PMC
August 2020

The effect of compound kushen injection on cancer cells: Integrated identification of candidate molecular mechanisms.

PLoS One 2020 30;15(7):e0236395. Epub 2020 Jul 30.

Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.

Traditional Chinese Medicine (TCM) preparations are often extracts of single or multiple herbs containing hundreds of compounds, and hence it has been difficult to study their mechanisms of action. Compound Kushen Injection (CKI) is a complex mixture of compounds extracted from two medicinal plants and has been used in Chinese hospitals to treat cancer for over twenty years. To demonstrate that a systematic analysis of molecular changes resulting from complex mixtures of bioactives from TCM can identify a core set of differentially expressed (DE) genes and a reproducible set of candidate pathways. We used in vitro cancer models to measure the effect of CKI on cell cycle phases and apoptosis, and correlated those phenotypes with CKI induced changes in gene expression. We treated two cancer cell lines with or without CKI and assessed the resulting phenotypes by employing cell viability and proliferation assays. Based on these results, we carried out high-throughput transcriptome data analysis to identify genes and candidate pathways perturbed by CKI. We integrated these differential gene expression results with previously reported results and carried out validation of selected differentially expressed genes. CKI induced cell-cycle arrest and apoptosis in the cancer cell lines tested. In these cells CKI also altered the expression of 363 core candidate genes associated with cell cycle, apoptosis, DNA replication/repair, and various cancer pathways. Of these, 7 are clinically relevant to cancer diagnosis or therapy, 14 are cell cycle regulators, and most of these 21 candidates are downregulated by CKI. Comparison of our core candidate genes to a database of plant medicinal compounds and their effects on gene expression identified one-to-one, one-to-many and many-to-many regulatory relationships between compounds in CKI and DE genes. By identifying genes and promising candidate pathways associated with CKI treatment based on our transcriptome-based analysis, we have shown that this approach is useful for the systematic analysis of molecular changes resulting from complex mixtures of bioactives.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236395PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392229PMC
September 2020

Accelerated brain aging towards transcriptional inversion in a zebrafish model of the K115fs mutation of human PSEN2.

PLoS One 2020 24;15(1):e0227258. Epub 2020 Jan 24.

Alzheimer's Disease Genetics Laboratory, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.

Background: The molecular changes involved in Alzheimer's disease (AD) progression remain unclear since we cannot easily access antemortem human brains. Some non-mammalian vertebrates such as the zebrafish preserve AD-relevant transcript isoforms of the PRESENILIN genes lost from mice and rats. One example is PS2V, the alternative transcript isoform of the PSEN2 gene. PS2V is induced by hypoxia/oxidative stress and shows increased expression in late onset, sporadic AD brains. A unique, early onset familial AD mutation of PSEN2, K115fs, mimics the PS2V coding sequence suggesting that forced, early expression of PS2V-like isoforms may contribute to AD pathogenesis. Here we use zebrafish to model the K115fs mutation to investigate the effects of forced PS2V-like expression on the transcriptomes of young adult and aged adult brains.

Methods: We edited the zebrafish genome to model the K115fs mutation. To explore its effects at the molecular level, we analysed the brain transcriptome and proteome of young (6-month-old) and aged (24-month-old) wild type and heterozygous mutant female sibling zebrafish. Finally, we used gene co-expression network analysis (WGCNA) to compare molecular changes in the brains of these fish to human AD.

Results: Young heterozygous mutant fish show transcriptional changes suggesting accelerated brain aging and increased glucocorticoid signalling. These early changes precede a transcriptional 'inversion' that leads to glucocorticoid resistance and other likely pathological changes in aged heterozygous mutant fish. Notably, microglia-associated immune responses regulated by the ETS transcription factor family are altered in both our zebrafish mutant model and in human AD. The molecular changes we observe in aged heterozygous mutant fish occur without obvious histopathology and possibly in the absence of Aβ.

Conclusions: Our results suggest that forced expression of a PS2V-like isoform contributes to immune and stress responses favouring AD pathogenesis. This highlights the value of our zebrafish genetic model for exploring molecular mechanisms involved in AD pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980398PMC
May 2020

A New Strategy for Identifying Mechanisms of Drug-drug Interaction Using Transcriptome Analysis: Compound Kushen Injection as a Proof of Principle.

Sci Rep 2019 11 4;9(1):15889. Epub 2019 Nov 4.

Zhendong Australia - China Centre for Molecular Chinese Medicine, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, 5005, Australia.

Drug-drug interactions (DDIs), especially with herbal medicines, are complex, making it difficult to identify potential molecular mechanisms and targets. We introduce a workflow to carry out DDI research using transcriptome analysis and interactions of a complex herbal mixture, Compound Kushen Injection (CKI), with cancer chemotherapy drugs, as a proof of principle. Using CKI combined with doxorubicin or 5-Fu on cancer cells as a model, we found that CKI enhanced the cytotoxic effects of doxorubicin on A431 cells while protecting MDA-MB-231 cells treated with 5-Fu. We generated and analysed transcriptome data from cells treated with single treatments or combined treatments and our analysis showed that opposite directions of regulation for pathways related to DNA synthesis and metabolism which appeared to be the main reason for different effects of CKI when used in combination with chemotherapy drugs. We also found that pathways related to organic biosynthetic and metabolic processes might be potential targets for CKI when interacting with doxorubicin and 5-Fu. Through co-expression analysis correlated with phenotype results, we selected the MYD88 gene as a candidate major regulator for validation as a proof of concept for our approach. Inhibition of MYD88 reduced antagonistic cytotoxic effects between CKI and 5-Fu, indicating that MYD88 is an important gene in the DDI mechanism between CKI and chemotherapy drugs. These findings demonstrate that our pipeline is effective for the application of transcriptome analysis to the study of DDIs in order to identify candidate mechanisms and potential targets.
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http://dx.doi.org/10.1038/s41598-019-52375-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828681PMC
November 2019

Yiqi Chutan Tang Reduces Gefitinib-Induced Drug Resistance in Non-Small-Cell Lung Cancer by Targeting Apoptosis and Autophagy.

Cytometry A 2020 01 14;97(1):70-77. Epub 2019 Aug 14.

First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510000, Guangdong Province, China.

High incidence and mortality rates for non-small-cell lung cancer (NSCLC) lead to low survival rates. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are commonly first prescribed for NSCLC patients with EGFR mutations. However, most patients with sensitizing EGFR mutations become resistant to EGFR-TKI after 9-13 months treatment. Yiqi Chutan Tang (YQCT) has been prescribed as a treatment to this issue for over 20 years. In this report, high-performance liquid chromatography (HPLC) analysis, flow cytometry, western blot analysis, and functional annotation analysis were applied to uncover the molecular mechanisms of YQCT. Our results show the application of YQCT reduces gefitinib-induced drug resistance, induces slight cell cycle arrest, enhances gefitinib-induced apoptosis, and activates the autophagy. These results indicate that at the molecular level YQCT can reduce drug resistance and improve anti-cancer effects when associated with gefitinib, which could be a result of enhancement of apoptosis and autophagy in the EGFR-TKI resistant cells of NSCLC. This research provides a new treatment strategy for patients with EGFR-TKI resistance in NSCLC. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.
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http://dx.doi.org/10.1002/cyto.a.23869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004076PMC
January 2020

Understanding the Mechanistic Contribution of Herbal Extracts in Compound Kushen Injection With Transcriptome Analysis.

Front Oncol 2019 12;9:632. Epub 2019 Jul 12.

Zhendong Australia-China Centre for Molecular Chinese Medicine, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.

Herbal compatibility is the knowledge of which herbs to combine in traditional Chinese medicine (TCM) formulations. The lack of understanding of herbal compatibility is one of the key problems for the application and popularization of TCM in western society. Because of the chemical complexity of herbal medicines, it is simpler to begin to conduct compatibility research based on herbs rather than component plant secondary metabolites. We have used transcriptome analysis to explore the effects and interactions of two plant extracts (Kushen and Baituling) combined in Compound Kushen Injection (CKI). Based on shared chemical compounds and cytotoxicity comparisons, we found that both the major compounds in CKI, and the cytotoxicity effects of CKI were mainly derived from the extract of Kushen (). We generated and analyzed transcriptome data from MDA-MB-231 cells treated with single-herb extracts or CKI and results showed that Kushen contributed to the perturbation of the majority of cytotoxicity/cancer related pathways in CKI such as cell cycle and DNA replication. We also found that Baituling () could not only enhance the cytotoxic effects of Kushen in CKI, but also activate immune-related pathways. Our analyses predicted that IL-1β gene expression was upregulated by Baituling in CKI and we confirmed that IL-1β protein expression was increased using an ELISA assay. Altogether, these findings help to explain the rationale for combining Kushen and Baituling in CKI, and show that transcriptome analysis using single herb extracts is an effective method for understanding herbal compatibility in TCM.
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http://dx.doi.org/10.3389/fonc.2019.00632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660286PMC
July 2019

An effective drug sensitizing agent increases gefitinib treatment by down regulating PI3K/Akt/mTOR pathway and up regulating autophagy in non-small cell lung cancer.

Biomed Pharmacother 2019 Oct 13;118:109169. Epub 2019 Jul 13.

First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, PR China. Electronic address:

Gefitinib is one of commonly used first-line treatment options for patients with positive EGFR mutation in non-small cell lung cancer (NSCLC). However, most patients with gefitinib treatment relapse over time due to the loss of drug sensitivity. Compound Kushen injection (CKI) has been used to treat lung cancer, including EGFR-mutated NSCLC. In this report, we examined the anti-cancer and drug sensitivity increased activities of CKI in gefitinib less sensitive NSCLC cell lines H1650 and H1975. Bioinformatics analysis was applied to uncover gene regulation and molecular mechanisms of CKI. Our results indicated that when associating with gefitinib in a dose-dependent fashion, CKI demonstrated the ability to inhibit the proliferation and to increase the sensitivity to gefitinib treatment in gefitinib less sensitive cell lines. This could be the results of down regulation of the PI3K/Akt/mTOR pathway and up regulation of autophagy, which were identified as the potential primary targets of CKI to increase gefitinib treatment effect.
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http://dx.doi.org/10.1016/j.biopha.2019.109169DOI Listing
October 2019

Effect of Compound Kushen Injection, a Natural Compound Mixture, and Its Identified Chemical Components on Migration and Invasion of Colon, Brain, and Breast Cancer Cell Lines.

Front Oncol 2019 26;9:314. Epub 2019 Apr 26.

Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.

Traditional Chinese Medicines are promising sources of new agents for controlling cancer metastasis. Compound Kushen Injection (CKI), prepared from medicinal plants and , disrupts cell cycle and induces apoptosis in breast cancer; however, effects on migration and invasion remained unknown. CKI, fractionated mixtures, and isolated components were tested in migration assays with colon (HT-29, SW-480, DLD-1), brain (U87-MG, U251-MG), and breast (MDA-MB-231) cancer cell lines. Human embryonic kidney (HEK-293) and human foreskin fibroblast (HFF) served as non-cancerous controls. Wound closure, transwell invasion, and live cell imaging showed CKI reduced motility in all eight lines. Fractionation and reconstitution of CKI demonstrated combinations of compounds were required for activity. Live cell imaging confirmed CKI strongly reduced migration of HT-29 and MDA-MB-231 cells, moderately slowed brain cancer cells, and had a small effect on HEK-293. CKI uniformly blocked invasiveness through extracellular matrix. Apoptosis was increased by CKI in breast cancer but not in non-cancerous lines. Cell viability was unaffected by CKI in all cell lines. Transcriptomic analyses of MDA-MB-231indicated down-regulation of actin cytoskeletal and focal adhesion genes with CKI treatment, consistent with observed impairment of cell migration. The pharmacological complexity of CKI is important for effective blockade of cancer migration and invasion.
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http://dx.doi.org/10.3389/fonc.2019.00314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498862PMC
April 2019

Cell cycle, energy metabolism and DNA repair pathways in cancer cells are suppressed by Compound Kushen Injection.

BMC Cancer 2019 Jan 24;19(1):103. Epub 2019 Jan 24.

Department of Molecular and Biomedical Science, The University of Adelaide, North Terrace, Adelaide, 5005, South Australia, Australia.

Background: In this report we examine candidate pathways perturbed by Compound Kushen Injection (CKI), a Traditional Chinese Medicine (TCM) that we have previously shown to alter the gene expression patterns of multiple pathways and induce apoptosis in cancer cells.

Methods: We have measured protein levels in Hep G2 and MDA-MB-231 cells for genes in the cell cycle pathway, DNA repair pathway and DNA double strand breaks (DSBs) previously shown to have altered expression by CKI. We have also examined energy metabolism by measuring [ADP]/[ATP] ratio (cell energy charge), lactate production and glucose consumption. Our results demonstrate that CKI can suppress protein levels for cell cycle regulatory proteins and DNA repair while increasing the level of DSBs. We also show that energy metabolism is reduced based on reduced glucose consumption and reduced cellular energy charge.

Results: Our results validate these pathways as important targets for CKI. We also examined the effect of the major alkaloid component of CKI, oxymatrine and determined that it had no effect on DSBs, a small effect on the cell cycle and increased the cell energy charge.

Conclusions: Our results indicate that CKI likely acts through the effect of multiple compounds on multiple targets where the observed phenotype is the integration of these effects and synergistic interactions.
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http://dx.doi.org/10.1186/s12885-018-5230-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345000PMC
January 2019

Alters Expression of Energy Metabolism Genes and Prevents Cell Death in High-Glucose Loaded Mouse Embryos.

Evid Based Complement Alternat Med 2018 25;2018:2409471. Epub 2018 Jun 25.

School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia.

Background: (ZGW) is a classic formula in traditional chinese medicine (TCM). Previous studies have shown that it is beneficial for impaired glucose tolerance (IGT) of adults and the offspring as well. This study aimed to understand the molecular mechanisms of the efficacy of ZGW on IGT.

Methods: We used high-glucose loaded 2-cell stage mouse embryos as a model and took advantage of single-cell RNA sequencing technology to analyze the transcriptome of the model with or without ZGW. Differential gene expression analysis was performed with DESeq2.

Results: High glucose can downregulate genes in the ribosome pathway, while ZGW can reverse this inhibition and as a result prevent embryo cell death caused by high glucose. Furthermore, high glucose can affect sugar metabolism and influence mitochondrial function, but ZGW can promote sugar metabolism via the tricarboxylic acid cycle mainly through upregulating the genes in the respiratory chain and oxidative phosphorylation.

Conclusions: ZGW had a protective effect on embryonic cell death caused by glucose loading. The reversion of inhibition of ribosome pathway and regulation of mitochondrial energy metabolism are main effects of ZGW on high-glucose loaded embryos. This research not only revealed the global gene regulation changes of high glucose affecting 2-cell stage embryos but also provided insight into the potential molecular mechanisms of ZGW on the IGT model.
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http://dx.doi.org/10.1155/2018/2409471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036835PMC
June 2018

Horizontal transfer of BovB and L1 retrotransposons in eukaryotes.

Genome Biol 2018 07 9;19(1):85. Epub 2018 Jul 9.

Department of Genetics and Evolution, Biological Sciences, The University of Adelaide, Adelaide, SA, Australia.

Background: Transposable elements (TEs) are mobile DNA sequences, colloquially known as jumping genes because of their ability to replicate to new genomic locations. TEs can jump between organisms or species when given a vector of transfer, such as a tick or virus, in a process known as horizontal transfer. Here, we propose that LINE-1 (L1) and Bovine-B (BovB), the two most abundant TE families in mammals, were initially introduced as foreign DNA via ancient horizontal transfer events.

Results: Using analyses of 759 plant, fungal and animal genomes, we identify multiple possible L1 horizontal transfer events in eukaryotic species, primarily involving Tx-like L1s in marine eukaryotes. We also extend the BovB paradigm by increasing the number of estimated transfer events compared to previous studies, finding new parasite vectors of transfer such as bed bug, leech and locust, and BovB occurrences in new lineages such as bat and frog. Given that these transposable elements have colonised more than half of the genome sequence in today's mammals, our results support a role for horizontal transfer in causing long-term genomic change in new host organisms.

Conclusions: We describe extensive horizontal transfer of BovB retrotransposons and provide the first evidence that L1 elements can also undergo horizontal transfer. With the advancement of genome sequencing technologies and bioinformatics tools, we anticipate our study to be a valuable resource for inferring horizontal transfer from large-scale genomic data.
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http://dx.doi.org/10.1186/s13059-018-1456-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036668PMC
July 2018

Transposable elements and gene expression during the evolution of amniotes.

Mob DNA 2018 12;9:17. Epub 2018 Jun 12.

1School of Biological Sciences, The University of Adelaide, North Terrace, Adelaide, 5005 Australia.

Background: Transposable elements (TEs) are primarily responsible for the DNA losses and gains in genome sequences that occur over time within and between species. TEs themselves evolve, with clade specific LTR/ERV, LINEs and SINEs responsible for the bulk of species-specific genomic features. Because TEs can contain regulatory motifs, they can be exapted as regulators of gene expression. While TE insertions can provide evolutionary novelty for the regulation of gene expression, their overall impact on the evolution of gene expression is unclear. Previous investigators have shown that tissue specific gene expression in amniotes is more similar across species than within species, supporting the existence of conserved developmental gene regulation. In order to understand how species-specific TE insertions might affect the evolution/conservation of gene expression, we have looked at the association of gene expression in six tissues with TE insertions in six representative amniote genomes.

Results: A novel bootstrapping approach has been used to minimise the conflation of effects of repeat types on gene expression. We compared the expression of orthologs containing recent TE insertions to orthologs that contained older TE insertions, and the expression of non-orthologs containing recent TE insertions to non-orthologs with older TE insertions. Both orthologs and non-orthologs showed significant differences in gene expression associated with TE insertions. TEs were found associated with species-specific changes in gene expression, and the magnitude and direction of expression changes were noteworthy. Overall, orthologs containing species-specific TEs were associated with lower gene expression, while in non-orthologs, non-species specific TEs were associated with higher gene expression. Exceptions were SINE elements in human and chicken, which had an opposite association with gene expression compared to other species.

Conclusions: Our observed species-specific associations of TEs with gene expression support a role for TEs in speciation/response to selection by species. TEs do not exhibit consistent associations with gene expression and observed associations can vary depending on the age of TE insertions. Based on these observations, it would be prudent to refrain from extrapolating these and previously reported associations to distantly related species.
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http://dx.doi.org/10.1186/s13100-018-0124-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998507PMC
June 2018

Genome-Wide Analysis of the Association of Transposable Elements with Gene Regulation Suggests that Alu Elements Have the Largest Overall Regulatory Impact.

J Comput Biol 2018 06 30;25(6):551-562. Epub 2018 Apr 30.

1 School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , Shanghai, China .

Nearly half of the human genome is made up of transposable elements (TEs), and there is evidence that TEs are involved in gene regulation. In this study, we have integrated publicly available genomic, epigenetic, and transcriptomic data to investigate this in a genome-wide manner. A bootstrapping statistical method was applied to minimize confounder effects from different repeat types. Our results show that although most TE classes are primarily associated with reduced gene expression, Alu elements are associated with upregulated gene expression. Furthermore, Alu elements had the highest probability of any TE class contributing to regulatory regions of any type defined by chromatin state. This suggests a general model where clade-specific short interspersed elements (SINEs) may contribute more to gene regulation than ancient/ancestral TEs. Our exhaustive analysis has extended and updated our understanding of TEs in terms of their global impact on gene regulation and suggests that the most recently derived types of TEs, that is, clade- or species-specific SINES, have the greatest overall impact on gene regulation.
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http://dx.doi.org/10.1089/cmb.2017.0228DOI Listing
June 2018

Divergent genome evolution caused by regional variation in DNA gain and loss between human and mouse.

PLoS Comput Biol 2018 04 20;14(4):e1006091. Epub 2018 Apr 20.

Department of Genetics and Evolution, The University of Adelaide, North Tce, Adelaide, Australia.

The forces driving the accumulation and removal of non-coding DNA and ultimately the evolution of genome size in complex organisms are intimately linked to genome structure and organisation. Our analysis provides a novel method for capturing the regional variation of lineage-specific DNA gain and loss events in their respective genomic contexts. To further understand this connection we used comparative genomics to identify genome-wide individual DNA gain and loss events in the human and mouse genomes. Focusing on the distribution of DNA gains and losses, relationships to important structural features and potential impact on biological processes, we found that in autosomes, DNA gains and losses both followed separate lineage-specific accumulation patterns. However, in both species chromosome X was particularly enriched for DNA gain, consistent with its high L1 retrotransposon content required for X inactivation. We found that DNA loss was associated with gene-rich open chromatin regions and DNA gain events with gene-poor closed chromatin regions. Additionally, we found that DNA loss events tended to be smaller than DNA gain events suggesting that they were able to accumulate in gene-rich open chromatin regions due to their reduced capacity to interrupt gene regulatory architecture. GO term enrichment showed that mouse loss hotspots were strongly enriched for terms related to developmental processes. However, these genes were also located in regions with a high density of conserved elements, suggesting that despite high levels of DNA loss, gene regulatory architecture remained conserved. This is consistent with a model in which DNA gain and loss results in turnover or "churning" in regulatory element dense regions of open chromatin, where interruption of regulatory elements is selected against.
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http://dx.doi.org/10.1371/journal.pcbi.1006091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931693PMC
April 2018

Superior ab initio identification, annotation and characterisation of TEs and segmental duplications from genome assemblies.

PLoS One 2018 14;13(3):e0193588. Epub 2018 Mar 14.

School of Biological Sciences, The University of Adelaide, Adelaide, SA 5005, Australia.

Transposable Elements (TEs) are mobile DNA sequences that make up significant fractions of amniote genomes. However, they are difficult to detect and annotate ab initio because of their variable features, lengths and clade-specific variants. We have addressed this problem by refining and developing a Comprehensive ab initio Repeat Pipeline (CARP) to identify and cluster TEs and other repetitive sequences in genome assemblies. The pipeline begins with a pairwise alignment using krishna, a custom aligner. Single linkage clustering is then carried out to produce families of repetitive elements. Consensus sequences are then filtered for protein coding genes and then annotated using Repbase and a custom library of retrovirus and reverse transcriptase sequences. This process yields three types of family: fully annotated, partially annotated and unannotated. Fully annotated families reflect recently diverged/young known TEs present in Repbase. The remaining two types of families contain a mixture of novel TEs and segmental duplications. These can be resolved by aligning these consensus sequences back to the genome to assess copy number vs. length distribution. Our pipeline has three significant advantages compared to other methods for ab initio repeat identification: 1) we generate not only consensus sequences, but keep the genomic intervals for the original aligned sequences, allowing straightforward analysis of evolutionary dynamics, 2) consensus sequences represent low-divergence, recently/currently active TE families, 3) segmental duplications are annotated as a useful by-product. We have compared our ab initio repeat annotations for 7 genome assemblies to other methods and demonstrate that CARP compares favourably with RepeatModeler, the most widely used repeat annotation package.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193588PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851578PMC
June 2018

A comprehensive genomic history of extinct and living elephants.

Proc Natl Acad Sci U S A 2018 03 26;115(11):E2566-E2574. Epub 2018 Feb 26.

Broad Institute of MIT and Harvard, Cambridge, MA 02142.

Elephantids are the world's most iconic megafaunal family, yet there is no comprehensive genomic assessment of their relationships. We report a total of 14 genomes, including 2 from the American mastodon, which is an extinct elephantid relative, and 12 spanning all three extant and three extinct elephantid species including an ∼120,000-y-old straight-tusked elephant, a Columbian mammoth, and woolly mammoths. Earlier genetic studies modeled elephantid evolution via simple bifurcating trees, but here we show that interspecies hybridization has been a recurrent feature of elephantid evolution. We found that the genetic makeup of the straight-tusked elephant, previously placed as a sister group to African forest elephants based on lower coverage data, in fact comprises three major components. Most of the straight-tusked elephant's ancestry derives from a lineage related to the ancestor of African elephants while its remaining ancestry consists of a large contribution from a lineage related to forest elephants and another related to mammoths. Columbian and woolly mammoths also showed evidence of interbreeding, likely following a latitudinal cline across North America. While hybridization events have shaped elephantid history in profound ways, isolation also appears to have played an important role. Our data reveal nearly complete isolation between the ancestors of the African forest and savanna elephants for ∼500,000 y, providing compelling justification for the conservation of forest and savanna elephants as separate species.
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http://dx.doi.org/10.1073/pnas.1720554115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856550PMC
March 2018

Correction to: Combined gene expression and proteomic analysis of EGF induced apoptosis in A431 cells suggests multiple pathways trigger apoptosis.

Apoptosis 2018 01;23(1):92

School of Molecular & Biomedical Science, The University of Adelaide, Adelaide, SA, Australia.

The original version of this article unfortunately contained a mistake. The affiliation of first author Dr. Ibrahim Alanazi was incorrect.
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http://dx.doi.org/10.1007/s10495-017-1431-xDOI Listing
January 2018

Similar Evolutionary Trajectories for Retrotransposon Accumulation in Mammals.

Genome Biol Evol 2017 09;9(9):2336-2353

Department of Genetics and Evolution, The University of Adelaide, South Australia, Australia.

The factors guiding retrotransposon insertion site preference are not well understood. Different types of retrotransposons share common replication machinery and yet occupy distinct genomic domains. Autonomous long interspersed elements accumulate in gene-poor domains and their nonautonomous short interspersed elements accumulate in gene-rich domains. To determine genomic factors that contribute to this discrepancy we analyzed the distribution of retrotransposons within the framework of chromosomal domains and regulatory elements. Using comparative genomics, we identified large-scale conserved patterns of retrotransposon accumulation across several mammalian genomes. Importantly, retrotransposons that were active after our sample-species diverged accumulated in orthologous regions. This suggested a similar evolutionary interaction between retrotransposon activity and conserved genome architecture across our species. In addition, we found that retrotransposons accumulated at regulatory element boundaries in open chromatin, where accumulation of particular retrotransposon types depended on insertion size and local regulatory element density. From our results, we propose a model where density and distribution of genes and regulatory elements canalize retrotransposon accumulation. Through conservation of synteny, gene regulation and nuclear organization, mammalian genomes with dissimilar retrotransposons follow similar evolutionary trajectories.
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http://dx.doi.org/10.1093/gbe/evx179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610350PMC
September 2017

Long read reference genome-free reconstruction of a full-length transcriptome from reveals transcript variants involved in bioactive compound biosynthesis.

Cell Discov 2017 29;3:17031. Epub 2017 Aug 29.

Department of Genetics and Evolution, School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia.

also known as Huangqi in China, is one of the most widely used medicinal herbs in Traditional Chinese Medicine. Traditional Chinese Medicine formulations from have been used to treat a wide range of illnesses, such as cardiovascular disease, type 2 diabetes, nephritis and cancers. Pharmacological studies have shown that immunomodulating, anti-hyperglycemic, anti-inflammatory, antioxidant and antiviral activities exist in the extract of . Therefore, characterising the biosynthesis of bioactive compounds in , such as Astragalosides, Calycosin and Calycosin-7-O-β-d-glucoside, is of particular importance for further genetic studies of . In this study, we reconstructed the full-length transcriptomes from leaf and root tissues using PacBio Iso-Seq long reads. We identified 27 975 and 22 343 full-length unique transcript models in each tissue respectively. Compared with previous studies that used short read sequencing, our reconstructed transcripts are longer, and are more likely to be full-length and include numerous transcript variants. Moreover, we also re-characterised and identified potential transcript variants of genes involved in Astragalosides, Calycosin and Calycosin-7-O-β-d-glucoside biosynthesis. In conclusion, our study provides a practical pipeline to characterise the full-length transcriptome for species without a reference genome and a useful genomic resource for exploring the biosynthesis of active compounds in .
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http://dx.doi.org/10.1038/celldisc.2017.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573880PMC
August 2017

Seed weight differences between wild and domesticated soybeans are associated with specific changes in gene expression.

Plant Cell Rep 2017 Sep 26;36(9):1417-1426. Epub 2017 Jun 26.

State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330031, Jiangxi, China.

Key Message: Our study systematically explored potential genes and molecular pathways as candidates for differences in seed weight resulting from soybean domestication. In addition, potential contributions of lncRNAs to seed weight were also investigated. Soybeans have a long history of domestication in China, and there are several significant phenotypic differences between cultivated and wild soybeans, for example, seeds of cultivars are generally larger and heavier than those from wild accessions. We analyzed seed transcriptomes from thirteen soybean samples, including six landraces and seven wild accessions using strand-specific RNA sequencing. Differentially expressed genes related to seed weight were identified, and some of their homologs were associated with seed development in Arabidopsis. We also identified 1251 long intergenic noncoding RNAs (lincRNAs), 243 intronic RNAs and 81 antisense lncRNAs de novo from these soybean transcriptomes. We then profiled the expression patterns of lncRNAs in cultivated and wild soybean seeds, and found that transcript levels of a number of lncRNAs were sample-specific. Moreover, gene transcript and lincRNA co-expression network analysis showed that some soybean lincRNAs might have functional roles as they were hubs of co-expression modules. In conclusion, this study systematically explored potential genes and molecular pathways as candidates for differences in seed weight resulting from soybean domestication, and will provide a useful future resource for molecular breeding of soybeans.
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http://dx.doi.org/10.1007/s00299-017-2165-5DOI Listing
September 2017

Understanding the Effectiveness of Natural Compound Mixtures in Cancer through Their Molecular Mode of Action.

Int J Mol Sci 2017 Mar 17;18(3). Epub 2017 Mar 17.

Department of Genetics and Evolution, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Many approaches to cancer management are often ineffective due to adverse reactions, drug resistance, or inadequate target specificity of single anti-cancer agents. In contrast, a combinatorial approach with the application of two or more anti-cancer agents at their respective effective dosages can achieve a synergistic effect that boosts cytotoxicity to cancer cells. In cancer, aberrant apoptotic pathways allow cells that should be killed to survive with genetic abnormalities, leading to cancer progression. Mutations in apoptotic mechanism arising during the treatment of cancer through cancer progression can consequently lead to chemoresistance. Natural compound mixtures that are believed to have multiple specific targets with minimal acceptable side-effects are now of interest to many researchers due to their cytotoxic and chemosensitizing activities. Synergistic interactions within a drug mixture enhance the search for potential molecular targets in cancer cells. Nonetheless, biased/flawed scientific evidence from natural products can suggest false positive therapeutic benefits during drug screening. In this review, we have taken these factors into consideration when discussing the evidence for these compounds and their synergistic therapeutic benefits in cancer. While there is limited evidence for clinical efficacy for these mixtures, in vitro data suggest that these preparations merit further investigation, both in vitro and in vivo.
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http://dx.doi.org/10.3390/ijms18030656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372668PMC
March 2017

A novel hypothesis-unbiased method for Gene Ontology enrichment based on transcriptome data.

PLoS One 2017 15;12(2):e0170486. Epub 2017 Feb 15.

School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

Gene Ontology (GO) classification of statistically significantly differentially expressed genes is commonly used to interpret transcriptomics data as a part of functional genomic analysis. In this approach, all significantly expressed genes contribute equally to the final GO classification regardless of their actual expression levels. Gene expression levels can significantly affect protein production and hence should be reflected in GO term enrichment. Genes with low expression levels can also participate in GO term enrichment through cumulative effects. In this report, we have introduced a new GO enrichment method that is suitable for multiple samples and time series experiments that uses a statistical outlier test to detect GO categories with special patterns of variation that can potentially identify candidate biological mechanisms. To demonstrate the value of our approach, we have performed two case studies. Whole transcriptome expression profiles of Salmonella enteritidis and Alzheimer's disease (AD) were analysed in order to determine GO term enrichment across the entire transcriptome instead of a subset of differentially expressed genes used in traditional GO analysis. Our result highlights the key role of inflammation related functional groups in AD pathology as granulocyte colony-stimulating factor receptor binding, neuromedin U binding, and interleukin were remarkably upregulated in AD brain when all using all of the gene expression data in the transcriptome. Mitochondrial components and the molybdopterin synthase complex were identified as potential key cellular components involved in AD pathology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170486PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310883PMC
August 2017

Transposable elements (TEs) contribute to stress-related long intergenic noncoding RNAs in plants.

Plant J 2017 Apr;90(1):133-146

Shanghai Center for Plant Stress Biology, Shanghai Institute for Biological Science, Chinese Academy of Sciences, Shanghai, 200032, China.

Noncoding RNAs have been extensively described in plant and animal transcriptomes by using high-throughput sequencing technology. Of these noncoding RNAs, a growing number of long intergenic noncoding RNAs (lincRNAs) have been described in multicellular organisms, however the origins and functions of many lincRNAs remain to be explored. In many eukaryotic genomes, transposable elements (TEs) are widely distributed and often account for large fractions of plant and animal genomes yet the contribution of TEs to lincRNAs is largely unknown. By using strand-specific RNA-sequencing, we profiled the expression patterns of lincRNAs in Arabidopsis, rice and maize, and identified 47 611 and 398 TE-associated lincRNAs (TE-lincRNAs), respectively. TE-lincRNAs were more often derived from retrotransposons than DNA transposons and as retrotransposon copy number in both rice and maize genomes so did TE-lincRNAs. We validated the expression of these TE-lincRNAs by strand-specific RT-PCR and also demonstrated tissue-specific transcription and stress-induced TE-lincRNAs either after salt, abscisic acid (ABA) or cold treatments. For Arabidopsis TE-lincRNA11195, mutants had reduced sensitivity to ABA as demonstrated by longer roots and higher shoot biomass when compared to wild-type. Finally, by altering the chromatin state in the Arabidopsis chromatin remodelling mutant ddm1, unique lincRNAs including TE-lincRNAs were generated from the preceding untranscribed regions and interestingly inherited in a wild-type background in subsequent generations. Our findings not only demonstrate that TE-associated lincRNAs play important roles in plant abiotic stress responses but lincRNAs and TE-lincRNAs might act as an adaptive reservoir in eukaryotes.
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http://dx.doi.org/10.1111/tpj.13481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514416PMC
April 2017

LINEs between Species: Evolutionary Dynamics of LINE-1 Retrotransposons across the Eukaryotic Tree of Life.

Genome Biol Evol 2016 12 14;8(11):3301-3322. Epub 2016 Dec 14.

School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia

LINE-1 (L1) retrotransposons are dynamic elements. They have the potential to cause great genomic change because of their ability to 'jump' around the genome and amplify themselves, resulting in the duplication and rearrangement of regulatory DNA. Active L1, in particular, are often thought of as tightly constrained, homologous and ubiquitous elements with well-characterized domain organization. For the past 30 years, model organisms have been used to define L1s as 6-8 kb sequences containing a 5'-UTR, two open reading frames working harmoniously in cis, and a 3'-UTR with a polyA tail. In this study, we demonstrate the remarkable and overlooked diversity of L1s via a comprehensive phylogenetic analysis of elements from over 500 species from widely divergent branches of the tree of life. The rapid and recent growth of L1 elements in mammalian species is juxtaposed against the diverse lineages found in other metazoans and plants. In fact, some of these previously unexplored mammalian species (e.g. snub-nosed monkey, minke whale) exhibit L1 retrotranspositional 'hyperactivity' far surpassing that of human or mouse. In contrast, non-mammalian L1s have become so varied that the current classification system seems to inadequately capture their structural characteristics. Our findings illustrate how both long-term inherited evolutionary patterns and random bursts of activity in individual species can significantly alter genomes, highlighting the importance of L1 dynamics in eukaryotes.
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http://dx.doi.org/10.1093/gbe/evw243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203782PMC
December 2016

Identification of candidate anti-cancer molecular mechanisms of Compound Kushen Injection using functional genomics.

Oncotarget 2016 10;7(40):66003-66019

Department of Genetics and Evolution, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Compound Kushen Injection (CKI) has been clinically used in China for over 15 years to treat various types of solid tumours. However, because such Traditional Chinese Medicine (TCM) preparations are complex mixtures of plant secondary metabolites, it is essential to explore their underlying molecular mechanisms in a systematic fashion. We have used the MCF-7 human breast cancer cell line as an initial in vitro model to identify CKI induced changes in gene expression. Cells were treated with CKI for 24 and 48 hours at two concentrations (1 and 2 mg/mL total alkaloids), and the effect of CKI on cell proliferation and apoptosis were measured using XTT and Annexin V/Propidium Iodide staining assays respectively. Transcriptome data of cells treated with CKI or 5-Fluorouracil (5-FU) for 24 and 48 hours were subsequently acquired using high-throughput Illumina RNA-seq technology. In this report we show that CKI inhibited MCF-7 cell proliferation and induced apoptosis in a dose-dependent fashion. We integrated and applied a series of transcriptome analysis methods, including gene differential expression analysis, pathway over-representation analysis, de novo identification of long non-coding RNAs (lncRNA) as well as co-expression network reconstruction, to identify candidate anti-cancer molecular mechanisms of CKI. Multiple pathways were perturbed and the cell cycle was identified as the potential primary target pathway of CKI in MCF-7 cells. CKI may also induce apoptosis in MCF-7 cells via a p53 independent mechanism. In addition, we identified novel lncRNAs and showed that many of them might be expressed as a response to CKI treatment.
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http://dx.doi.org/10.18632/oncotarget.11788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323210PMC
October 2016

In depth analysis of the Sox4 gene locus that consists of sense and natural antisense transcripts.

Data Brief 2016 Jun 17;7:282-90. Epub 2016 Feb 17.

Department of Molecular Pathology, The Institute of Medical and Veterinary Science and The Hanson Institute, P.O. Box 14 Rundle Mall Post Office, Adelaide, SA 5000, Australia; School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA 5005, Australia.

SRY (Sex Determining Region Y)-Box 4 or Sox4 is an important regulator of the pan-neuronal gene expression during post-mitotic cell differentiation within the mammalian brain. Sox4 gene locus has been previously characterized with multiple sense and overlapping natural antisense transcripts [1], [2]. Here we provide accompanying data on various analyses performed and described in Ling et al. [2]. The data include a detail description of various features found at Sox4 gene locus, additional experimental data derived from RNA-Fluorescence in situ Hybridization (RNA-FISH), Western blotting, strand-specific reverse-transcription quantitative polymerase chain reaction (RT-qPCR), gain-of-function and in situ hybridization (ISH) experiments. All the additional data provided here support the existence of an endogenous small interfering- or PIWI interacting-like small RNA known as Sox4_sir3, which origin was found within the overlapping region consisting of a sense and a natural antisense transcript known as Sox4ot1.
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http://dx.doi.org/10.1016/j.dib.2016.01.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773576PMC
June 2016
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