Changes In Gene Regulation Research Articles

Tap the sap - investigation of latex-bearing plants in the search of potential anticancer biopharmaceuticals.

Latex-bearing plants have been in the research spotlight for the past couple of decades. Since ancient times their extracts have been used in folk medicine to treat various illnesses. Currently they serve as promising candidates for cancer treatment. Up to date there have been several in vitro and in vivo studies related to the topic of cytotoxicity and anticancer activity of extracts from latex-bearing plants towards various cell types. The number of clinical studies still remains scarce, however, over the years the number is systematically increasing. To the best of our knowledge, the scientific community is still lacking in a recent review summarizing the research on the topic of cytotoxicity and anticancer activity of latex-bearing plant extracts. Therefore, the aim of this paper is to review the current knowledge on in vitro and in vivo studies, which focus on the cytotoxicity and anticancer activities of latex-bearing plants. The vast majority of the studies are in vitro, however, the interest in this topic has resulted in the substantial growth of the number of in vivo studies, leading to a promising number of plant species whose latex can potentially be tested in clinical trials. The paper is divided into sections, each of them focuses on specific latex-bearing plant family representatives and their potential anticancer activity, which in some instances is comparable to that induced by commonly used therapeutics currently available on the market. The cytotoxic effect of the plant's crude latex, its fractions or isolated compounds, is analyzed, along with a study of cell apoptosis, chromatin condensation, DNA damage, changes in gene regulation and morphology changes, which can be observed in cell post plant extract addition. The in vivo studies go beyond the molecular level by showing significant reduction of the tumor growth and volume in animal models. Additionally, we present data regarding plant-mediated biosynthesis of nanoparticles, which is regarded as a new branch in plant latex research. It is solely based on the green-synthesis approach, which presents an interesting alternative to chemical-based nanoparticle synthesis. We have analyzed the cytotoxic effect of these particles on cells. Data regarding the cytotoxicity of such particles raises their potential to be involved in the design of novel cancer therapies, which further underlines the significance of latex-bearing plants in biotechnology. Throughout the course of this review, we concluded that plant latex is a rich source of many compounds, which can be further investigated and applied in the design of anticancer pharmaceuticals. The molecules, to which this cytotoxic effect can be attributed, include alkaloids, flavonoids, tannins, terpenoids, proteases, nucleases and many novel compounds, which still remain to be characterized. They have been studied extensively in both in vitro and in vivo studies, which provide an excellent starting point for their rapid transfer to clinical studies in the near future. The comprehensive study of molecules from latex-bearing plants can result in finding a promising alternative to several pharmaceuticals on the market and help unravel the molecular mode of action of latex-based preparations.

Gapless genome assembly of azalea and multi-omics investigation into divergence between two species with distinct flower color.

The genus Rhododendron (Ericaceae), with more than 1000 species highly diverse in flower color, is providing distinct ornamental values and a model system for flower color studies. Here, we investigated the divergence between two parental species with different flower color widely used for azalea breeding. Gapless genome assembly was generated for the yellow-flowered azalea, Rhododendron molle. Comparative genomics found recent proliferation of long terminal repeat retrotransposons (LTR-RTs), especially Gypsy, has resulted in a 125Mb (19%) genome size increase in species-specific regions, and a significant amount of dispersed gene duplicates (13402) and pseudogenes (17 437). Metabolomic assessment revealed that yellow flower coloration is attributed to the dynamic changes of carotenoids/flavonols biosynthesis and chlorophyll degradation. Time-ordered gene co-expression networks (TO-GCNs) and the comparison confirmed the metabolome and uncovered the specific gene regulatory changes underpinning the distinct flower pigmentation. B3 and ERF TFs were found dominating the gene regulation of carotenoids/flavonols characterized pigmentation in R. molle, while WRKY, ERF, WD40, C2H2, and NAC TFs collectively regulated the anthocyanins characterized pigmentation in the red-flowered R simsii. This study employed a multi-omics strategy in disentangling the complex divergence between two important azaleas and provided references for further functional genetics and molecular breeding.

Shared Patterns of Gene Expression and Protein Evolution Associated with Adaptation to Desert Environments in Rodents.

Desert specialization has arisen multiple times across rodents and is often associated with a suite of convergent phenotypes, including modification of the kidneys to mitigate water loss. However, the extent to which phenotypic convergence in desert rodents is mirrored at the molecular level is unknown. Here, we sequenced kidney mRNA and assembled transcriptomes for three pairs of rodent species to search for shared differences in gene expression and amino acid sequence associated with adaptation to deserts. We conducted phylogenetically independent comparisons between a desert specialist and a non-desert relative in three families representing ∼70 million years of evolution. Overall, patterns of gene expression faithfully recapitulated the phylogeny of these six taxa providing a strong evolutionary signal in levels of mRNA abundance. We also found that 8.6% of all genes showed shared patterns of expression divergence between desert and non-desert taxa, much of which likely reflects convergent evolution, and representing more than expected by chance under a model of independent gene evolution. In addition to these shared changes, we observed many species-pair-specific changes in gene expression indicating that instances of adaptation to deserts include a combination of unique and shared changes. Patterns of protein evolution revealed a small number of genes showing evidence of positive selection, the majority of which did not show shared changes in gene expression. Overall, our results suggest that convergent changes in gene regulation play an important role in the complex trait of desert adaptation in rodents.

Cri du chat syndrome patients have DNA methylation changes in genes linked to symptoms of the disease

BackgroundCri du chat (also called 5p deletion, or monosomy 5p) syndrome is a genetic disease caused by deletions of various lengths in the short (p) arm of chromosome 5. Genetic analysis and phenotyping have been used to suggest dose-sensitive genes in this region that may cause symptoms when a gene copy is lost, but the heterogeneity of symptoms for patients with similar deletions complicates the picture. The epigenetics of the syndrome has only recently been looked at with DNA methylation measurements of blood from a single patient, suggesting epigenetic changes in these patients. Here, we conduct the deepest epigenetic analysis of the syndrome to date with DNA methylation analysis of eight Cri du chat patients with sibling- and age-matched controls.ResultsThe genome-wide patterns of DNA methylation in the blood of Cri du chat patients reveal distinct changes compared to controls. In the p-arm of chromosome 5 where patients are hemizygous, we find stronger changes in methylation of CpG sites than what is seen in the rest of the genome, but this effect is less pronounced in gene regulatory sequences. Gene set enrichment analysis using patient DNA methylation changes in gene promoters revealed enrichment of genes controlling embryonic development and genes linked to symptoms which are among the most common symptoms of Cri du chat syndrome: developmental delay and microcephaly. Importantly, this relative enrichment is not driven by changes in the methylation of genes on chromosome 5. CpG sites linked to these symptoms where Cri du chat patients have strong DNA methylation changes are enriched for binding of the polycomb EZH2 complex, H3K27me3, and H3K4me2, indicating changes to bivalent promoters, known to be central to embryonic developmental processes.ConclusionsFinding DNA methylation changes in the blood of Cri du chat patients linked to the most common symptoms of the syndrome is suggestive of epigenetic changes early in embryonic development that may be contributing to the development of symptoms. However, with the present data we cannot conclude about the sequence of events between DNA methylation changes and other cellular functions—the observed differences could be directly driving epigenetic changes, a result of other epigenetic changes, or they could be a reflection of other gene regulatory changes such as changed gene expression levels. We do not know which gene(s) on the p-arm of chromosome 5 that causes epigenetic changes when hemizygous, but an important contribution from this work is making the pool of possible causative genes smaller.

Differential Regulation of Genes by the Glucogenic Hormone Asprosin in Ovarian Cancer.

Background: Ovarian cancer (OvCa) is one of the most lethal forms of gynaecological malignancy. Altered energy metabolism and increased aerobic glycolysis in OvCa are hallmarks that demand attention. The glucogenic hormone asprosin is often dysregulated in metabolic disorders such as insulin resistance, diabetes (type 2 and gestational), and preeclampsia. Despite association with metabolic disorders, its role in energy metabolism within the tumour microenvironment is yet to be explored. Here, we study the role of asprosin in OvCa using transcriptomics and expand on functional studies with clinical samples. Methods: RNA sequencing, functional gene enrichment analysis, Western blotting and ImageStream. Results: Following treatment with 100 nM of asprosin, the serous OvCa cell line, SKOV-3, displayed 160 and 173 gene regulatory changes, at 4 and 12 h respectively, when compared with control samples (p < 0.05 and Log2FC > 1). In addition to energy metabolism and glucose-related pathways, asprosin was shown to alter pathways associated with cell communication, TGF-β signalling, and cell proliferation. Moreover, asprosin was shown to induce phosphorylation of ERK1/2 in the same in vitro model. Using liquid biopsies, we also report for novel expression of asprosin’s predicted receptors OR4M1 and TLR4 in cancer-associated circulating cells; with significant reduction seen between pre-chemotherapy and end of first line chemotherapy, in addition to patients under maintenance with bevacizumab +/− olaparib for OR4M1. Conclusions: In relation to OvCa, asprosin appears to regulate numerous signalling pathways in-vitro. The prognostic potential of OR4M1 in liquid biopsies should also be explored further.

Changes in the Transcriptome-Associated Co-Expression Profile of Embryonic External Ear Development After the BMP5 Gene Mutation.

This study aimed to perform an association analysis of the full transcriptome in Bmp5 short-ear mice during the development of the external ear in mouse embryos using advanced sequencing techniques. To understand the changes in gene regulation and expression of BMP5 gene mutations involved in the external ear embryonic development of mice, external ear tissues of mouse embryos developed to E15.5 and E17.5 were obtained using a BMP5 short-ear mouse model. The association analysis of the full transcriptome mainly involved the analysis of lncRNA and mRNA associations, the analysis of lncRNA and miRNA associations, the analysis of miRNA and mRNA associations, the analysis of circRNA and mRNA associations and circRNA, miRNA, and mRNA associations. The results showed that regulation of the full transcriptome is associated with external ear development in BMP5 short-ear mouse embryos, and some key regulatory changes in full transcriptome after BMP5 gene point mutation are different. This study will provide a new clue to investigate the mechanism underlying the regulation of mouse external ear development by the full transcriptome.

Bmp5 Mutation Alters mRNA Expression During External Ear Development.

To understand changes in gene regulation and mRNA expression in external ear development, we used a bone morphogenetic protein 5 (BMP5) short-ear mouse model. External ear tissues at E15.5 and E17.5 were collected, and mRNA expression profiles were analyzed. Upregulated and downregulated mRNA expression was identified using find_circ and CIRI2 software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed using the differentially expressed mRNAs. Alterations in related signal pathways were identified from the upregulated and downregulated mRNA transcripts. The results showed a correlation between the mRNA expression during external ear development in BMP5 short-ear mice, including key regulatory mRNA changes after point mutations of the Bmp5 gene. This study provides evidence for the mechanism underlying mRNA regulation during external ear development. Changes in mRNA expression profiles also provide clues for future studies regarding the regulatory mechanisms underlying external ear development.

M6A RNA Methylation-Based Epitranscriptomic Modifications in Plasticity-Related Genes via miR-124-C/EBPα-FTO-Transcriptional Axis in the Hippocampus of Learned Helplessness Rats.

Impaired synaptic plasticity has been linked to dynamic gene regulatory network changes. Recently, gene regulation has been introduced with the emerging concept of unique N6-methyladenosine (m6A)-based reversible transcript methylation. In this study, we tested whether m6A RNA methylation may potentially serve as a link between the stressful insults and altered expression of plasticity-related genes. Expression of plasticity genes Nr3c1, Creb1, Ntrk2; m6A-modifying enzymes Fto, methyltransferase like (Mettl)-3 and 14; DNA methylation enzymes Dnmt1, Dnmt3a; transcription factor C/ebp-α; and miRNA-124-3p were determined by quantitative polymerase chain reaction (qPCR) in the hippocampus of rats that showed susceptibility to develop stress-induced depression (learned helplessness). M6A methylation of plasticity-related genes was determined following m6A mRNA immunoprecipitation. Chromatin immunoprecipitation was used to examine the endogenous binding of C/EBP-α to the Fto promoter. MiR-124-mediated post-transcriptional inhibition of Fto via C/EBPα was determined using an in vitro model. Hippocampus of learned helplessness rats showed downregulation of Nr3c1, Creb1, and Ntrk2 along with enrichment in their m6A methylation. A downregulation in demethylating enzyme Fto and upregulation in methylating enzyme Mettl3 were also noted. The Fto promoter was hypomethylated due to the lower expression of Dnmt1 and Dnmt3a. At the same time, there was a lower occupancy of transcription factor C/EBPα on the Fto promoter. Conversely, C/ebp-α transcript was downregulated via induced miR-124-3p expression. Our study mechanistically linked defective C/EBP-α-FTO-axis, epigenetically influenced by induced expression of miR-124-3p, in modifying m6A enrichment in plasticity-related genes. This could potentially be linked with abnormal neuronal plasticity in depression.

Genome-wide identification and transcriptome analysis of the heavy metal-associated (HMA) gene family in Tartary buckwheat and their regulatory roles under cadmium stress

Heavy metal-associated (HMA) genes are those related to heavy metal transport and detoxification in plants. HMA genes have not been reported in Tartary buckwheat so far. In this study, we accessed the HMA genes of Tartary buckwheat by genome-wide identification for the first time. A total of 56 HMA genes were identified, including 36 ATX1 (antioxidant protein1) genes, 13 HIPP (heavy metal-associated isoprenylated plant protein) genes, and 7 P1B-ATPase (P1B-type adenosine triphosphatase) genes. These gene structures, motif compositions, chromosomal distribution, phylogenetic relationship, duplication events, interaction networks, cis-acting elements, and transcriptional expression under cadmium (Cd) stress were investigated. Among them, genes in HIPP and ATX1 subfamilies were more closely related. The 56 HMA genes were involved in the regulation of metal ion transport and homeostasis by binding metal ions, likely triggered by signals transducted by plant hormones. Fifteen of these HMA genes played regulatory roles under Cd stress. FtP1bA1 was identified to be a core gene involved in the defense regulation of Cd stress. Our results provide not only the first overview and characteristics of HMA genes in the whole genome of Tartary buckwheat but also a valuable reference for the functional analysis of HMA genes under Cd stress. Understanding changes in gene regulation induced by Cd stress lays the foundation for breeding resistant varieties.

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

Depression and anxiety are major global health burdens. Although SSRIs targeting the serotonergic system are prescribed over 200 million times annually, they have variable therapeutic efficacy and side effects, and mechanisms of action remain incompletely understood. Here, we comprehensively characterise the molecular landscape of gene regulatory changes associated with fluoxetine, a widely-used SSRI. We performed multimodal analysis of SSRI response in 27 mammalian brain regions using 310 bulk RNA-seq and H3K27ac ChIP-seq datasets, followed by in-depth characterisation of two hippocampal regions using single-cell RNA-seq (20 datasets). Remarkably, fluoxetine induced profound region-specific shifts in gene expression and chromatin state, including in the nucleus accumbens shell, locus coeruleus and septal areas, as well as in more well-studied regions such as the raphe and hippocampal dentate gyrus. Expression changes were strongly enriched at GWAS loci for depression and antidepressant drug response, stressing the relevance to human phenotypes. We observed differential expression at dozens of signalling receptors and pathways, many of which are previously unknown. Single-cell analysis revealed stark differences in fluoxetine response between the dorsal and ventral hippocampal dentate gyri, particularly in oligodendrocytes, mossy cells and inhibitory neurons. Across diverse brain regions, integrative omics analysis consistently suggested increased energy metabolism via oxidative phosphorylation and mitochondrial changes, which we corroborated in vitro; this may thus constitute a shared mechanism of action of fluoxetine. Similarly, we observed pervasive chromatin remodelling signatures across the brain. Our study reveals unexpected regional and cell type-specific heterogeneity in SSRI action, highlights under-studied brain regions that may play a major role in antidepressant response, and provides a rich resource of candidate cell types, genes, gene regulatory elements and pathways for mechanistic analysis and identifying new therapeutic targets for depression and anxiety.

Embryonic Arsenic Exposure Triggers Long-Term Behavioral Impairment with Metabolite Alterations in Zebrafish.

Arsenic trioxide (As2O3) is a ubiquitous heavy metal in the environment. Exposure to this toxin at low concentrations is unremarkable in developing organisms. Nevertheless, understanding the underlying mechanism of its long-term adverse effects remains a challenge. In this study, embryos were initially exposed to As2O3 from gastrulation to hatching under semi-static conditions. Results showed dose-dependent increased mortality, with exposure to 30–40 µM As2O3 significantly reducing tail-coiling and heart rate at early larval stages. Surviving larvae after 30 µM As2O3 exposure showed deficits in motor behavior without impairment of anxiety-like responses at 6 dpf and a slight impairment in color preference behavior at 11 dpf, which was later evident in adulthood. As2O3 also altered locomotor function, with a loss of directional and color preference in adult zebrafish, which correlated with changes in transcriptional regulation of adsl, shank3a, and tsc1b genes. During these processes, As2O3 mainly induced metabolic changes in lipids, particularly arachidonic acid, docosahexaenoic acid, prostaglandin, and sphinganine-1-phosphate in the post-hatching period of zebrafish. Overall, this study provides new insight into the potential mechanism of arsenic toxicity leading to long-term learning impairment in zebrafish and may benefit future risk assessments of other environmental toxins of concern.

Oral squamous cell carcinoma gene patterns connected with RNA methylation for prognostic prediction.

To determine whether m6A/m1A/m5C/m7G/m6Am/Ψ-related genes influence the prognosis of a patient with oral squamous cell carcinoma. We investigated the changes in regulatory genes using publicly available data from The Cancer Genome Atlas. Consensus clustering by RNA methylation-related regulators was used to describe oral squamous cell carcinomas (OSCCs). Then, we developed the prediction model. The tumor microenvironment was investigated using ESTIMATE. Gene set enrichment analysis was used to determine whether pathways or cell types were enriched in different groups. The association between the model and immune-related risk scores was investigated using correlation analysis. We found 22 gene signatures in this analysis and then developed a predictive model that reveals the genes that are highly connected to the overall survival of OSCC patients. The survival and death rates were substantially different in the two groups (high and low risk) classified by the risk scores. The validation cohort verified the phenotypic diversity and prognostic effects of these genes. Our data reveal that immune cell infiltration, genetic mutation, and survival potential in OSCC patients are linked to m6A/m1A/m5C/m7G/m6Am/Ψ-related genes, and we constructed a dependable prognostic model for OSCC patients.

A Pilot Study on Peptidylarginine Deiminases and Protein Deimination in Animal Cancers across Vertebrate Species.

PADs are a group of calcium-dependent enzymes that play key roles in inflammatory pathologies and have diverse roles in cancers. PADs cause irreversible post-translational modification of arginine to citrulline, leading to changes in protein function in different cellular compartments. PAD isozyme diversity differs throughout phylogeny in chordates, with five PAD isozymes in mammals, three in birds, and one in fish. While the roles for PADs in various human cancers are mounting (both in regards to cancer progression and epigenetic regulation), investigations into animal cancers are scarce. The current pilot-study therefore aimed at assessing PAD isozymes in a range of animal cancers across the phylogeny tree. In addition, the tissue samples were assessed for total protein deimination and histone H3 deimination (CitH3), which is strongly associated with human cancers and also indicative of gene regulatory changes and neutrophil extracellular trap formation (NETosis). Cancers were selected from a range of vertebrate species: horse, cow, reindeer, sheep, pig, dog, cat, rabbit, mink, hamster, parrot, and duck. The cancers chosen included lymphoma, kidney, lung, testicular, neuroendocrine, anaplastic, papilloma, and granulosa cell tumour. Immunohistochemical analysis revealed that CitH3 was strongly detected in all of the cancers assessed, while pan-deimination detection was overall low. Both PAD2 and PAD3 were the most predominantly expressed PADs across all of the cancers assessed, while PAD1, PAD4, and PAD6 were overall expressed at lower, albeit varying, levels. The findings from this pilot study provide novel insights into PAD-mediated roles in different cancers across a range of vertebrate species and may aid in the understanding of cancer heterogeneity and cancer evolution.

Gene regulation on extrachromosomal DNA.

Oncogene amplification on extrachromosomal DNA (ecDNA) is prevalent in human cancer and is associated with poor outcomes. Clonal, megabase-sized circular ecDNAs in cancer are distinct from nonclonal, small sub-kilobase-sized DNAs that may arise during normal tissue homeostasis. ecDNAs enable profound changes in gene regulation beyond copy-number gains. An emerging principle of ecDNA regulation is the formation of ecDNA hubs: micrometer-sized nuclear structures of numerous copies of ecDNAs tethered by proteins in spatial proximity. ecDNA hubs enable cooperative and intermolecular sharing of DNA regulatory elements for potent and combinatorial gene activation. The 3D context of ecDNA shapes its gene expression potential, selection for clonal heterogeneity among ecDNAs, distribution through cell division, and reintegration into chromosomes. Technologies for studying gene regulation and structure of ecDNA are starting to answer long-held questions on the distinct rules that govern cancer genes beyond chromosomes.

Bmp5 Mutation Alters miRNA Expression During Embryonic External Ear Development.

To understand the changes in gene regulation and expression of MicroRNA (miRNA) involved in external mouseear embryonic development after point mutation of the Bmp5 gene, the outer ear tissues of developed E15.5 and E17.5 mouse embryos were obtained using a Bmp5 short ear mouse model, and the changes in miRNA expression profiles were detected. Changes in miRNA expression in the experimental and control groups were identified during Bmp5 short ear mouse embryo development at E15.5 and E17.5. GO and Kyoto Encyclopedia of Genes and Genomes functional annotations were performed on differentially expressed miRNAs. Multiple signal pathways related to miRNA expression were enhanced during the development of E15.5 and E17.5 embryos of Bmp5 short-ear mice. Based on the basic characteristics of miRNAs, this study aimed to determine the differential expression of miRNAs in Bmp5 short-ear mice during the development of external ear embryos using advanced sequencing techniques. The results showed differences in some key regulatory miRNA changes after point mutations in the Bmp5 gene. This study provides new insights into the mechanism by which miRNAs regulate the development of the external mouse ear. Changes in miRNA expression profiles can also provide clues for studying the biological regulatory mechanism of external ear embryonic development.

How thermal challenges change gene regulation in the songbird brain and gonad: Implications for sexual selection in our changing world.

In a rapidly warming world, exposure to high temperatures may impact fitness, but the gene regulatory mechanisms that link sublethal heat to sexually selected traits are not well understood, particularly in endothermic animals. Our experiment used zebra finches (Taeniopygia guttata), songbirds that experience extreme temperature fluctuations in their native Australia. We exposed captive males to an acute thermal challenge (43°C) compared with thermoneutral (35°C) and lower (27°C) temperatures. We found significantly more heat dissipation behaviours at 43°C, a temperature previously shown to reduce song production and fertility, and more heat retention behaviours at 27°C. Next, we characterized transcriptomic responses in tissues important for mating effort-the posterior telencephalon, for its role in song production, and the testis, for its role in fertility and hormone production. Differential expression of hundreds of genes in the testes, but few in the brain, suggests the brain is less responsive to extreme temperatures. Nevertheless, gene network analyses revealed that expression related to dopaminergic signalling in the brain covaried with heat dissipation behaviours, providing a mechanism by which temporary thermal challenges may alter motivational circuits for song production. In both brain and testis, we observed correlations between thermally sensitive gene networks and individual differences in thermoregulatory behaviour. Although we cannot directly relate these gene regulatory changes to mating success, our results suggest that individual variation in response to thermal challenges could impact sexually selected traits in a warming world.

Longitudinal RNA Sequencing of Skin and DRG Neurons in Mice with Paclitaxel-Induced Peripheral Neuropathy.

Paclitaxel-induced peripheral neuropathy is a condition of nerve degeneration induced by chemotherapy, which afflicts up to 70% of treated patients. Therapeutic interventions are unavailable due to an incomplete understanding of the underlying mechanisms. We previously discovered that major physiological changes in the skin underlie paclitaxel-induced peripheral neuropathy in zebrafish and rodents. The precise molecular mechanisms are only incompletely understood. For instance, paclitaxel induces the upregulation of MMP-13, which, when inhibited, prevents axon degeneration. To better understand other gene regulatory changes induced by paclitaxel, we induced peripheral neuropathy in mice following intraperitoneal injection either with vehicle or paclitaxel every other day four times total. Skin and dorsal root ganglion neurons were collected based on distinct behavioural responses categorised as “pain onset” (d4), “maximal pain” (d7), “beginning of pain resolution” (d11), and “recovery phase” (d23) for comparative longitudinal RNA sequencing. The generated datasets validate previous discoveries and reveal additional gene expression changes that warrant further validation with the goal to aid in the development of drugs that prevent or reverse paclitaxel-induced peripheral neuropathy.

From the archives: Genetic determinants of trait measurement errors, gene regulatory changes between maize and sorghum, and a tissue-specific regulatory element.

From the archives: Genetic determinants of trait measurement errors, gene regulatory changes between maize and sorghum, and a tissue-specific regulatory element.

Inferring Signatures of Positive Selection in Whole-Genome Sequencing Data: An Overview of Haplotype-Based Methods.

Signatures of positive selection in the genome are a characteristic mark of adaptation that can reveal an ongoing, recent, or ancient response to environmental change throughout the evolution of a population. New sources of food, climate conditions, and exposure to pathogens are only some of the possible sources of selective pressure, and the rise of advantageous genetic variants is a crucial determinant of survival and reproduction. In this context, the ability to detect these signatures of selection may pinpoint genetic variants that are responsible for a significant change in gene regulation, gene expression, or protein synthesis, structure, and function. This review focuses on statistical methods that take advantage of linkage disequilibrium and haplotype determination to reveal signatures of positive selection in whole-genome sequencing data, showing that they emerge from different descriptions of the same underlying event. Moreover, considerations are provided around the application of these statistics to different species, their suitability for ancient DNA, and the usefulness of discovering variants under selection for biomedicine and public health in an evolutionary medicine framework.

Chromatin structure predicts survival in glioma patients

The pathological changes in epigenetics and gene regulation that accompany the progression of low-grade to high-grade gliomas are under-studied. The authors use a large set of paired atac-seq and RNA-seq data from surgically resected glioma specimens to infer gene regulatory relationships in glioma. Thirty-eight glioma patient samples underwent atac-seq sequencing and 16 samples underwent additional RNA-seq analysis. Using an atac-seq/RNA-seq correlation matrix, atac-seq peaks were paired with genes based on high correlation values (|r2| > 0.6). Samples clustered by IDH1 status but not by grade. Surprisingly there was a trend for IDH1 mutant samples to have more peaks. The majority of peaks are positively correlated with survival and positively correlated with gene expression. Constructing a model of the top six atac-seq peaks created a highly accurate survival prediction model (r2 = 0.68). Four of these peaks were still significant after controlling for age, grade, pathology, IDH1 status and gender. Grade II, III, and IV (primary) samples have similar transcription factors and gene modules. However, grade IV (recurrent) samples have strikingly few peaks. Patient-derived glioma cultures showed decreased peak counts following radiation indicating that this may be radiation-induced. This study supports the notion that IDH1 mutant and IDH1 wildtype gliomas have different epigenetic landscapes and that accessible chromatin sites mapped by atac-seq peaks tend to be positively correlated with expression. The data in this study leads to a new model of treatment response wherein glioma cells respond to radiation therapy by closing open regions of DNA.