scholarly journals A SINE-VNTR-Alu in the LRIG2 Promoter Is Associated with Gene Expression at the Locus

2020 ◽  
Vol 21 (22) ◽  
pp. 8486
Author(s):  
Ashley Hall ◽  
Anni K. Moore ◽  
Dena G. Hernandez ◽  
Kimberley J. Billingsley ◽  
Vivien J. Bubb ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Genomic Variation ◽  
Insertion Polymorphism ◽  
Rna Seq ◽  
The North ◽  
Allele Dosage ◽  
Brain Expression ◽  
Epigenetic Modulation ◽  
Leucine Rich Repeats ◽  
Human Specific

The hominid SINE-VNTR-Alu (SVA) retrotransposons represent a repertoire of genomic variation which could have significant effects on genome function. A human-specific SVA in the promoter region of the gene leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2), which we termed SVA_LRIG2, is a common retrotransposon insertion polymorphism (RIP), defined as an element which is polymorphic for its presence or absence in the genome. We hypothesised that this RIP might be associated with differential levels of expression of LRIG2. The RIP genotype of SVA_LRIG2 was determined in a subset of frontal cortex DNA samples from the North American Brain Expression Consortium (NABEC) cohort and was imputed for a larger set of that cohort. Utilising available frontal cortex total RNA-seq and CpG methylation data for this cohort, we observed that increased allele dosage of SVA_LRIG2 was non-significantly associated with a decrease in transcription from the region and significantly associated with increased methylation of the CpG probe nearest to SVA_LRIG2, i.e., SVA_LRIG2 is a significant methylation quantitative trait loci (mQTL) at the LRIG2 locus. These data are consistent with SVA_LRIG2 being a transcriptional regulator, which in part may involve epigenetic modulation.

scholarly journals A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer’s disease

2021 ◽  
Author(s):  
Vega García-Escudero ◽  
Daniel Ruiz-Gabarre ◽  
Ricardo Gargini ◽  
Mar Pérez ◽  
Esther García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Rna Seq ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Post Translational Modifications ◽  
Protein Levels ◽  
Tau Isoform ◽  
Human Specific

AbstractTauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer’s patients’ brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer’s disease and other tauopathies.

scholarly journals Natural cryptic variation in epigenetic modulation of an embryonic gene regulatory network

2020 ◽  
Vol 117 (24) ◽  
pp. 13637-13646 ◽  
Author(s):  
Chee Kiang Ewe ◽  
Yamila N. Torres Cleuren ◽  
Sagen E. Flowers ◽  
Geneva Alok ◽  
Russell G. Snell ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Phenotypic Diversity ◽  
Epigenetic Modification ◽  
Genomic Variation ◽  
Bzip Transcription Factor ◽  
Rnai Pathway ◽  
Cryptic Variation ◽  
Organ Systems ◽  
Gene Regulatory ◽  
Epigenetic Modulation

Gene regulatory networks (GRNs) that direct animal embryogenesis must respond to varying environmental and physiological conditions to ensure robust construction of organ systems. While GRNs are evolutionarily modified by natural genomic variation, the roles of epigenetic processes in shaping plasticity of GRN architecture are not well understood. The endoderm GRN inCaenorhabditis elegansis initiated by the maternally supplied SKN-1/Nrf2 bZIP transcription factor; however, the requirement for SKN-1 in endoderm specification varies widely among distinctC. eleganswild isotypes, owing to rapid developmental system drift driven by accumulation of cryptic genetic variants. We report here that heritable epigenetic factors that are stimulated by transient developmental diapause also underlie cryptic variation in the requirement for SKN-1 in endoderm development. This epigenetic memory is inherited from the maternal germline, apparently through a nuclear, rather than cytoplasmic, signal, resulting in a parent-of-origin effect (POE), in which the phenotype of the progeny resembles that of the maternal founder. The occurrence and persistence of POE varies between different parental pairs, perduring for at least 10 generations in one pair. This long-perduring POE requires piwi-interacting RNA (piRNA) function and the germline nuclear RNA interference (RNAi) pathway, as well as MET-2 and SET-32, which direct histone H3K9 trimethylation and drive heritable epigenetic modification. Such nongenetic cryptic variation may provide a resource of additional phenotypic diversity through which adaptation may facilitate evolutionary changes and shape developmental regulatory systems.

scholarly journals Antidepressant Mechanism Research of Acupuncture: Insights from a Genome-Wide Transcriptome Analysis of Frontal Cortex in Rats with Chronic Restraint Stress

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Yu Wang ◽  
Huili Jiang ◽  
Hong Meng ◽  
Jing Li ◽  
XinJing Yang ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Signaling Pathway ◽  
Restraint Stress ◽  
Enrichment Analysis ◽  
Differentially Expressed ◽  
Chronic Restraint Stress ◽  
Rna Seq ◽  
Toll Like Receptor ◽  
Genome Wide ◽  
Receptor Signaling Pathway

Major depressive disorder (MDD) is a chronic disease that adversely affects mood and cognition. In this study, we randomly divided the rats into control group (C), model group (M), fluoxetine group (F), and acupuncture group (A), used open-field test to ascertain whether acupuncture affects chronic restraint stress (CRS) induced depression-like behaviors of rats, and explored the antidepressant mechanism of acupuncture at the molecular level of transcriptome in the frontal cortex of CRS rats by RNA-sequencing (RNA-seq). According to differentially expressed genes (DEG) analysis, we identified 134, 46, and 89 response genes differentially expressed in C versus M, F versus M, and A versus M, respectively. Through Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, we identified the gene sets involved in extracellular space, inflammatory response, Toll-like receptor signaling pathway, chemokine signaling pathway, and TNF signaling pathway. In this study, RNA-seq technology was used to investigate the frontal cortex genome-wide transcriptomes in depression rats under CRS, which suggested that the antidepressant effect of acupuncture is effective and has a multitarget characteristic, which may be related to amino acid metabolism and inflammatory pathways, especially the Toll-like receptor signaling pathway, TNF signaling pathway, and NF-kappa B signaling pathway.

scholarly journals A human-specific switch of alternatively spliced AFMID isoforms contributes to TP53 mutations and tumor recurrence in hepatocellular carcinoma

2017 ◽  
Author(s):  
Kuan-Ting Lin ◽  
Wai-Kit Ma ◽  
Juergen Scharner ◽  
Yun-Ru Liu ◽  
Adrian R. Krainer
Keyword(s):  
Tumor Recurrence ◽  
De Novo ◽  
Mrna Splicing ◽  
Driver Mutations ◽  
Early Event ◽  
Rna Seq ◽  
Large Collection ◽  
Alternatively Spliced ◽  
Hcc Recurrence ◽  
Human Specific

AbstractPre-mRNA splicing can contribute to the switch of cell identity that occurs in carcinogenesis. Here we analyze a large collection of RNA-Seq datasets and report that splicing changes in hepatocyte-specific enzymes, such as AFMID and KHK, are associated with HCC patients’ survival and relapse. The switch of AFMID isoforms is an early event in HCC development, and is associated with driver mutations in TP53 and ARID1A. Finally, we show that the switch of AFMID isoforms is human-specific and not detectable in other species, including primates. The integrative analysis uncovers a mechanistic link between splicing switches, de novo NAD+ biosynthesis, driver mutations, and HCC recurrence.

scholarly journals Detection of Alu Exonization Events in Human Frontal Cortex From RNA-Seq Data

2021 ◽  
Vol 8 ◽  
Author(s):  
Liliana Florea ◽  
Lindsay Payer ◽  
Corina Antonescu ◽  
Guangyu Yang ◽  
Kathleen Burns
Keyword(s):  
Frontal Cortex ◽  
Large Scale ◽  
Reference Genome ◽  
Expression Patterns ◽  
Data Sets ◽  
Rna Seq ◽  
Mrna Isoforms ◽  
Specific Expression ◽  
Human Frontal Cortex ◽  
Alternatively Spliced

Alu exonization events functionally diversify the transcriptome, creating alternative mRNA isoforms and accounting for an estimated 5% of the alternatively spliced (skipped) exons in the human genome. We developed computational methods, implemented into a software called Alubaster, for detecting incorporation of Alu sequences in mRNA transcripts from large scale RNA-seq data sets. The approach detects Alu sequences derived from both fixed and polymorphic Alu elements, including Alu insertions missing from the reference genome. We applied our methods to 117 GTEx human frontal cortex samples to build and characterize a collection of Alu-containing mRNAs. In particular, we detected and characterized Alu exonizations occurring at 870 fixed Alu loci, of which 237 were novel, as well as hundreds of putative events involving Alu elements that are polymorphic variants or rare alleles not present in the reference genome. These methods and annotations represent a unique and valuable resource that can be used to understand the characteristics of Alu-containing mRNAs and their tissue-specific expression patterns.

scholarly journals Developmental programming: prenatal testosterone-induced epigenetic modulation and its effect on gene expression in sheep ovary†

2020 ◽  
Vol 102 (5) ◽  
pp. 1045-1054 ◽  
Author(s):  
Niharika Sinha ◽  
Sambit Roy ◽  
Binbin Huang ◽  
Jianrong Wang ◽  
Vasantha Padmanabhan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Silencing ◽  
Polycystic Ovary ◽  
Adult Life ◽  
Developmental Programming ◽  
Metabolic Dysfunction ◽  
Rna Seq ◽  
Sheep Model ◽  
Histone Marks ◽  
Epigenetic Modulation

Abstract Maternal perturbations or sub-optimal conditions during fetal development can predispose the offspring to diseases in adult life. Animal and human studies show that prenatal androgen excess may be an underlying cause of polycystic ovary syndrome (PCOS) later in life. In women, PCOS is a common fertility disorder with comorbid metabolic dysfunction. Here, using a sheep model of PCOS phenotype, we elucidate the epigenetic changes induced by prenatal (30–90 day) testosterone (T) treatment and its effect on gene expression in fetal day 90 (D90) and adult year 2 (Y2) ovaries. RNA-seq study shows 65 and 99 differentially regulated genes in prenatal T-treated fetal and adult ovaries, respectively. Interestingly, there were no differences in gene inducing histone marks H3K27ac, H3K9ac, and H3K4me3 or in gene silencing marks, H3K27me3 and H3K9me3 in the fetal D90 ovaries of control and excess T-exposed fetuses. In contrast, except for H3K4me3 and H3K27me3, all the other histone marks were upregulated in the prenatal T-treated adult Y2 ovary. Chromatin immunoprecipitation (ChIP) studies in adult Y2 ovaries established a direct relationship between the epigenetic modifications with the upregulated and downregulated genes obtained from RNA-seq. Results show increased gene inducing marks, H3K27ac and H3K9ac, on the promoter region of upregulated genes while gene silencing mark, H3K9me3, was also significantly increased on the downregulated genes. This study provides a mechanistic insight into prenatal T-induced developmental programming and its effect on ovarian gene expression that may contribute to reproductive dysfunction and development of PCOS in adult life.

scholarly journals Single-nuclei isoform RNA sequencing reveals combination patterns of transcript elements across human brain cell types

2021 ◽  
Author(s):  
Simon A Hardwick ◽  
Wen Hu ◽  
Anoushka Joglekar ◽  
Li Fan ◽  
Paul G Collier ◽  
...  
Keyword(s):  
Human Brain ◽  
Rna Sequencing ◽  
Cell Types ◽  
Brain Cell ◽  
Rna Seq ◽  
Cell Type ◽  
Long Read ◽  
Cell Type Specific ◽  
Adjacent Exon ◽  
Human Specific

Single-nuclei RNA-Seq is being widely employed to investigate cell types, especially of human brain and other frozen samples. In contrast to single-cell approaches, however, the majority of single-nuclei RNA counts originate from partially processed RNA leading to intronic cDNAs, thus hindering the investigation of complete isoforms. Here, using microfluidics, PCR-based artifact removal, target enrichment, and long-read sequencing, we developed single-nuclei isoform RNA-sequencing ('SnISOr-Seq'), and applied it to the analysis of human adult frontal cortex samples. We found that exons associated with autism exhibit coordinated and more cell-type specific inclusion than exons associated with schizophrenia or ALS. We discovered two distinct modes of combination patterns: first, those distinguishing cell types in the human brain. These are enriched in combinations of TSS-exon, exon-polyA site, and distant (non-adjacent) exon pairs. Second, those with all isoform combinations found within one neural cell type, which are enriched in adjacent exon pairs. Furthermore, adjacent exon pairs are predominantly mutually associated, while distant pairs are frequently mutually exclusive. Finally, we observed that human-specific exons are as tightly coordinated as conserved exons, pointing to an efficient evolutionary mechanism underpinning coordination. SnISOr-Seq opens the door to single-nuclei long-read isoform analysis in the human brain, and in any frozen, archived or hard-to-dissociate sample.

scholarly journals Molluscum Contagiosum Virus Transcriptome in Abortively Infected Cultured Cells and a Human Skin Lesion

2016 ◽  
Vol 90 (9) ◽  
pp. 4469-4480 ◽  
Author(s):  
Jorge D. Mendez-Rios ◽  
Zhilong Yang ◽  
Karl J. Erlandson ◽  
Jeffrey I. Cohen ◽  
Craig A. Martens ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skin Lesion ◽  
Human Skin ◽  
Cultured Cells ◽  
Skin Lesions ◽  
Molluscum Contagiosum ◽  
Rna Seq ◽  
Molluscum Contagiosum Virus ◽  
Human Specific

ABSTRACTMolluscum contagiosum virus (MOCV), the only circulating human-specific poxvirus, has a worldwide distribution and causes benign skin lesions that may persist for months in young children and severe infections in immunosuppressed adults. Studies of MOCV are restricted by the lack of an efficient animal model or a cell culture replication system. We used next-generation sequencing to analyze and compare polyadenylated RNAs from abortive MOCV infections of several cell lines and a human skin lesion. Viral RNAs were detected for 14 days after MOCV infection of cultured cells; however, there was little change in the RNA species during this time and a similar pattern occurred in the presence of an inhibitor of protein synthesis, indicating a block preventing postreplicative gene expression. Moreover, a considerable number of MOCV RNAs mapped to homologs of orthopoxvirus early genes, but few did so to homologs of intermediate or late genes. The RNAs made duringin vitroinfections represent a subset of RNAs detected in human skin lesions which mapped to homologs of numerous postreplicative as well as early orthopoxvirus genes. Transfection experiments using fluorescent protein and luciferase reporters demonstrated that vaccinia virus recognized MOCV intermediate and late promoters, indicating similar gene regulation. The specific recognition of the intermediate promoter in MOCV-infected cells provided evidence for the synthesis of intermediate transcription factors, which are products of early genes, but not for late transcription factors. Transcriptome sequencing (RNA-seq) and reporter gene assays may be useful for testing engineered cell lines and conditions that ultimately could provide anin vitroreplication system.IMPORTANCEThe inability to propagate molluscum contagiosum virus, which causes benign skin lesions in young children and more extensive infections in immunosuppressed adults, has constrained our understanding of the biology of this human-specific virus. In the present study, we characterized the RNAs synthesized in abortively infected cultured cells and a human skin lesion by next-generation sequencing. These studies provided an initial transcription map of the MOCV genome, suggested temporal regulation of gene expression, and indicated that thein vitroreplication block occurs prior to intermediate and late gene expression. RNA-seq and reporter assays, as described here, may help to further evaluate MOCV gene expression and define conditions that could enable MOCV replicationin vitro.

scholarly journals Virtue as the mean: Pan-human consensus genome significantly improves the accuracy of RNA-seq analyses

2020 ◽  
Author(s):  
Benjamin Kaminow ◽  
Sara Ballouz ◽  
Jesse Gillis ◽  
Alexander Dobin
Keyword(s):  
Reference Genome ◽  
Ground Truth ◽  
Genomic Variation ◽  
Rna Seq ◽  
Human Reference Genome ◽  
Transcript Quantification ◽  
Variant Information ◽  
The Mean ◽  
Modern Genomic ◽  
Genome Representation

The Human Reference Genome serves as the foundation for modern genomic analyses. However, in its present form, it does not adequately represent the vast genetic diversity of the human population. In this study, we explored the consensus genome as a potential successor of the current Reference genome, and assessed its effect on the accuracy of RNA-seq read alignment. In order to find the best haploid genome representation, we constructed consensus genomes at the Pan-human, Super-population and Population levels, utilizing variant information from the 1000 Genomes project. Using personal haploid genomes as the ground truth, we compared mapping errors for real RNA-seq reads aligned to the consensus genomes versus the Reference genome. For reads overlapping homozygous variants, we found that the mapping error decreased by a factor of ∼2-3 when the Reference was replaced with the Pan-human consensus genome. Interestingly, we also found that using more population-specific consensuses resulted in little to no increase over using the Pan-human consensus, suggesting a limit in the utility of incorporating more specific genomic variation. To assess the functional impact, we performed transcript expression quantification and found that the Pan-human consensus increases accuracy of transcript quantification for hundreds of transcripts.

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