Biology subjects

Adelson, D.

Publications and source records attributed to Adelson, D..

4 recordsLinked to original sources

bioRxiv2018

Cell Cycle, Energy Metabolism and DNA Repair Pathways in Cancer Cells are Suppressed by Compound Kushen Injection.

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. We have measured protein levels in HEPG2 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 [ADT]/[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. 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. 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.

cancer biology↗

bioRxiv2018

Transposable elements and gene expression during the evolution of amniotes

BackgroundTransposable elements (TEs) are primarily responsible for the changes 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 (human, opossum, platypus, anole lizard, bearded dragon and chicken).\n\nResultsWe have used a novel bootstrapping approach to minimise the conflation of effects of repeat types on gene expression. We compared the expression of orthologs containing different types of recent TE insertions to orthologs that contained older TE insertions and found significant differences in gene expression associated with TE insertions. Likewise, we compared the expression of non-ortholog genes containing different types of recent TE insertions to non-orthologs with older TE insertions and found significant differences in gene expression associated with TE insertions. As expected TEs were associated with species-specific changes in gene expression, but the magnitude and direction of change of expression changes were unexpected. Overall, orthologs containing clade specific TEs were associated with lower gene expression, while in non-orthologs, non clade-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.\n\nConclusionsOur 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.

evolutionary biology↗

bioRxiv2017

Genome-Wide Analysis Of Repetitive Elements Associated With Gene Regulation

Nearly half of the human genome is made up of transposable elements (TEs) and there is evidence that TEs are involved in gene regulation. Here, 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 the 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 up regulated gene expression. Furthermore, Alu elements had the highest probability of any TE class of contributing to regulatory regions of any type defined by chromatin state. This suggests a general model where clade specific SINEs may contribute more to gene regulation than ancient/ancestral TEs. Finally, non-coding regions were found to have a high probability of TE content within regulatory sequences, most notably in repressors. 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, i.e. clade or species specific SINES, have the greatest overall impact on gene regulation.

genomics↗

bioRxiv2017

Re-evaluating inheritance in genome evolution: widespread transfer of LINEs between species

Transposable elements (TEs) are mobile DNA sequences, colloquially known as jumping genes because of their ability to replicate to new genomic locations. Given a vector of transfer (e.g. tick or virus), TEs can jump further: between organisms or species in a process known as horizontal transfer (HT). 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 HT events. Using a 503-genome dataset, we identify multiple ancient L1 HT events in eukaryotes and provide evidence that L1s infiltrated the mammalian lineage after the monotreme-therian split. We also extend the BovB paradigm by increasing the number of estimated transfer events compared to previous studies, finding new potential blood-sucking parasite vectors and occurrences in new lineages (e.g. bats, frog). Given that these TEs make up nearly half of the genome sequence in todays mammals, our results provide the first evidence that HT can have drastic and long-term effects on the new host genomes. This revolutionizes our perception of genome evolution to consider external factors, such as the natural introduction of foreign DNA. With the advancement of genome sequencing technologies and bioinformatics tools, we anticipate our study to be the first of many large-scale phylogenomic analyses exploring the role of HT in genome evolution.\n\nSignificance statementLINE-1 (L1) elements occupy about half of most mammalian genomes (1), and they are believed to be strictly vertically inherited (2). Mutagenic L1 insertions are thought to account for approximately 1 of every 1000 random, disease-causing insertions in humans (4-7). Our research indicates that the very presence of L1s in humans, and other therian mammals, is due to an ancient transfer event - which has drastic implications for our perception of genome evolution. Using a machina analyses over 503 genomes, we trace the origins of L1 and BovB retrotransposons across the tree of life, and provide evidence of their long-term impact on eukaryotic evolution.

evolutionary biology↗