scholarly journals The landscape of human mutually exclusive splicing

2017 ◽  
Author(s):  
Klas Hatje ◽  
Ramon O. Vidal ◽  
Raza-Ur Rahman ◽  
Dominic Simm ◽  
Björn Hammesfahr ◽  
...  
Keyword(s):  
Strong Evidence ◽  
Human Disease ◽  
Biological Role ◽  
Rna Seq ◽  
Timothy Syndrome ◽  
Temporal Expression ◽  
Genome Wide ◽  
Spatio Temporal ◽  
Organismal Development

AbstractMutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genome-wide estimate of the extent and biological role of mutually exclusive splicing in humans we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA-seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than five-fold. The data provides strong evidence for the existence of large and multi-cluster MXEs in higher vertebrates and offers new insights into MXE splicing mechanics and evolution. Finally, MXEs are significantly enriched in pathogenic mutations and their spatio-temporal expression predicts human disease pathology.

scholarly journals FOXO1 mitigates the SMAD3/FOXL2C134W transcriptomic effect in a model of human adult granulosa cell tumor

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Christian Secchi ◽  
Paola Benaglio ◽  
Francesca Mulas ◽  
Martina Belli ◽  
Dwayne Stupack ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Chromatin Remodeling ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Rna Seq ◽  
Pathogenic Role ◽  
Rare Type ◽  
Cellular Models ◽  
Genome Wide

Abstract Background Adult granulosa cell tumor (aGCT) is a rare type of stromal cell malignant cancer of the ovary characterized by elevated estrogen levels. aGCTs ubiquitously harbor a somatic mutation in FOXL2 gene, Cys134Trp (c.402C < G); however, the general molecular effect of this mutation and its putative pathogenic role in aGCT tumorigenesis is not completely understood. We previously studied the role of FOXL2C134W, its partner SMAD3 and its antagonist FOXO1 in cellular models of aGCT. Methods In this work, seeking more comprehensive profiling of FOXL2C134W transcriptomic effects, we performed an RNA-seq analysis comparing the effect of FOXL2WT/SMAD3 and FOXL2C134W/SMAD3 overexpression in an established human GC line (HGrC1), which is not luteinized, and bears normal alleles of FOXL2. Results Our data shows that FOXL2C134W/SMAD3 overexpression alters the expression of 717 genes. These genes include known and novel FOXL2 targets (TGFB2, SMARCA4, HSPG2, MKI67, NFKBIA) and are enriched for neoplastic pathways (Proteoglycans in Cancer, Chromatin remodeling, Apoptosis, Tissue Morphogenesis, Tyrosine Kinase Receptors). We additionally expressed the FOXL2 antagonistic Forkhead protein, FOXO1. Surprisingly, overexpression of FOXO1 mitigated 40% of the altered genome-wide effects specifically related to FOXL2C134W, suggesting it can be a new target for aGCT treatment. Conclusions Our transcriptomic data provide novel insights into potential genes (FOXO1 regulated) that could be used as biomarkers of efficacy in aGCT patients.

scholarly journals Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

2020 ◽  
Vol 9 (4) ◽  
pp. 1096
Author(s):  
Jessica Gambardella ◽  
Angela Lombardi ◽  
Marco Bruno Morelli ◽  
John Ferrara ◽  
Gaetano Santulli
Keyword(s):  
Human Disease ◽  
Calcium Release ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genome Wide ◽  
Inositol 1,4,5 Trisphosphate ◽  
Human Disorders

Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.

scholarly journals Integrative genome-wide analysis reveals the role of WIP proteins in inhibition of growth and development

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Maria Victoria Gomez Roldan ◽  
Farhaj Izhaq ◽  
Marion Verdenaud ◽  
John Eleblu ◽  
Aimen Haraghi ◽  
...  
Keyword(s):  
Gene Networks ◽  
Growth Arrest ◽  
Reproductive Organs ◽  
Stress Signaling ◽  
Rna Seq ◽  
Genome Wide Analysis ◽  
Inhibition Of Growth ◽  
Genome Wide ◽  
Male Flowers

AbstractIn cucurbits, CmWIP1 is a master gene controlling sex determination. To bring new insight in the function of CmWIP1, we investigated two Arabidopsis WIP transcription factors, AtWIP1/TT1 and AtWIP2/NTT. Using an inducible system we showed that WIPs are powerful inhibitor of growth and inducer of cell death. Using ChIP-seq and RNA-seq we revealed that most of the up-regulated genes bound by WIPs display a W-box motif, associated with stress signaling. In contrast, the down-regulated genes contain a GAGA motif, a known target of polycomb repressive complex. To validate the role of WIP proteins in inhibition of growth, we expressed AtWIP1/TT1 in carpel primordia and obtained male flowers, mimicking CmWIP1 function in melon. Using other promoters, we further demonstrated that WIPs can trigger growth arrest of both vegetative and reproductive organs. Our data supports an evolutionary conserved role of WIPs in recruiting gene networks controlling growth and adaptation to stress.

scholarly journals Mirror bisulfite sequencing — a method for single-base resolution of hydroxymethylcytosine

2015 ◽  
Author(s):  
Xueguang Sun ◽  
Darany Tan ◽  
Tzu Hung Chung ◽  
Xi-Yu Jia
Keyword(s):  
Bisulfite Sequencing ◽  
Biological Role ◽  
Human Tissues ◽  
Bisulfite Conversion ◽  
Single Base ◽  
Cpg Site ◽  
Genome Wide ◽  
Single Base Resolution ◽  
Dna Strand

While the role of 5-methylcytosine has been well studied, the biological role of 5-hydroxymethylcytosine still remains unclear due to the limited methods available for single-base detection of 5-hydroxymethylcytosine (5hmC). Here, we present Mirror bisulfite sequencing detects 5-hydroxymethylcytosines at a single CpG site by synthesizing a DNA strand to mirror the parental strand. This semi-conservative duplex is sequentially treated with β-glucosyltransferase and M.SssI methylase. A glucosyl-5hmCpG in the parental strand inhibits methylation of the mirroring CpG site, and after bisulfite conversion, a thymine in the mirroring strand indicates a 5hmCpG site in the parental strand whereas a cytosine indicates a non-5hmC site. Using this method, the 5hmC levels of various human tissues and paired liver tissues were mapped genome-wide.

scholarly journals Genome-wide transcriptome analysis identifies alternative splicing regulatory network and key splicing factors in mouse and human psoriasis

2018 ◽  
Author(s):  
Jin Li ◽  
Peng Yu
Keyword(s):  
Alternative Splicing ◽  
Computational Analysis ◽  
Potential Role ◽  
Exon Skipping ◽  
Chronic Inflammatory Disease ◽  
Splicing Factors ◽  
The Novel ◽  
Rna Seq ◽  
Genome Wide

AbstractPsoriasis is a chronic inflammatory disease that affects the skin, nails, and joints. For understanding the mechanism of psoriasis, though, alternative splicing analysis has received relatively little attention in the field. Here, we developed and applied several computational analysis methods to study psoriasis. Using psoriasis mouse and human datasets, our differential alternative splicing analyses detected hundreds of differential alternative splicing changes. Our analysis of conservation revealed many exon-skipping events conserved between mice and humans. In addition, our splicing signature comparison analysis using the psoriasis datasets and our curated splicing factor perturbation RNA-Seq database, SFMetaDB, identified nine candidate splicing factors that may be important in regulating splicing in the psoriasis mouse model dataset. Three of the nine splicing factors were confirmed upon analyzing the human data. Our computational methods have generated predictions for the potential role of splicing in psoriasis. Future experiments on the novel candidates predicted by our computational analysis are expected to provide a better understanding of the molecular mechanism of psoriasis and to pave the way for new therapeutic treatments.

scholarly journals Viral discovery and diversity in trypanosomatid protozoa with a focus on relatives of the human parasiteLeishmania

2017 ◽  
Vol 115 (3) ◽  
pp. E506-E515 ◽  
Author(s):  
Danyil Grybchuk ◽  
Natalia S. Akopyants ◽  
Alexei Y. Kostygov ◽  
Aleksandras Konovalovas ◽  
Lon-Fye Lye ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Rna Polymerase ◽  
Human Disease ◽  
Rna Viruses ◽  
Biological Role ◽  
Viral Diversity ◽  
Rna Dependent Rna Polymerase ◽  
Human Parasite ◽  
Viral Lineage

Knowledge of viral diversity is expanding greatly, but many lineages remain underexplored. We surveyed RNA viruses in 52 cultured monoxenous relatives of the human parasiteLeishmania(CrithidiaandLeptomonas), as well as plant-infectingPhytomonas.Leptomonas pyrrhocoriswas a hotbed for viral discovery, carrying a virus (Leptomonas pyrrhocoris ostravirus 1) with a highly divergent RNA-dependent RNA polymerase missed by conventional BLAST searches, an emergent clade of tombus-like viruses, and an example of viral endogenization. A deep-branching clade of trypanosomatid narnaviruses was found, notable asLeptomonas seymouribearing Narna-like virus 1 (LepseyNLV1) have been reported in cultures recovered from patients with visceral leishmaniasis. A deep-branching trypanosomatid viral lineage showing strong affinities to bunyaviruses was termed “Leishbunyavirus” (LBV) and judged sufficiently distinct to warrant assignment within a proposed family termed “Leishbunyaviridae.” Numerous relatives of trypanosomatid viruses were found in insect metatranscriptomic surveys, which likely arise from trypanosomatid microbiota. Despite extensive sampling we found no relatives of the totivirusLeishmaniavirus(LRV1/2), implying that it was acquired at about the same time theLeishmaniabecame able to parasitize vertebrates. As viruses were found in over a quarter of isolates tested, many more are likely to be found in the >600 unsurveyed trypanosomatid species. Viral loss was occasionally observed in culture, providing potentially isogenic virus-free lines enabling studies probing the biological role of trypanosomatid viruses. These data shed important insights on the emergence of viruses within an important trypanosomatid clade relevant to human disease.

scholarly journals Elongin A regulates transcription in vivo through enhanced RNA polymerase processivity

2020 ◽  
pp. jbc.RA120.015876
Author(s):  
Yating Wang ◽  
Liming Hou ◽  
M. Behfar Ardehali ◽  
Robert E. Kingston ◽  
Brian D Dynlacht
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Transcriptional Elongation ◽  
Rna Seq ◽  
Transcription Profiles ◽  
Genome Wide ◽  
The Impact

Elongin is an RNA polymerase II (RNAPII)-associated factor that has been shown to stimulate transcriptional elongation in vitro. The Elongin complex is thought to be required for transcriptional induction in response to cellular stimuli and to ubiquitinate RNAPII in response to DNA damage. Yet the impact of the Elongin complex on transcription in vivo has not been well studied. Here, we performed comprehensive studies of the role of Elongin A, the largest subunit of the Elongin complex, on RNAPII transcription genome-wide. Our results suggest that Elongin A localizes to actively transcribed regions and potential enhancers, and the level of recruitment correlated with transcription levels. We also identified a large group of factors involved in transcription as Elongin A-associated factors. In addition, we found that loss of Elongin A leads to dramatically reduced levels of Ser2-phosphorylated, but not total, RNAPII, and cells depleted of Elongin A show stronger promoter RNAPII pausing, suggesting that Elongin A may be involved in the release of paused RNAPII. Our RNA-seq studies suggest that loss of Elongin A did not alter global transcription, and unlike prior in vitro studies, we did not observe a dramatic impact on RNAPII elongation rates in our cell-based nascent RNA-seq experiments upon Elongin A depletion. Taken together, our studies provide the first comprehensive analysis of the role of Elongin A in regulating transcription in vivo. Our studies also revealed that unlike prior in vitro findings, depletion of Elongin A has little impact on global transcription profiles and transcription elongation in vivo.

scholarly journals The ALOG family members OsG1L1 and OsG1L2 regulate inflorescence branching in rice

2021 ◽  
Author(s):  
Emanuela Franchini ◽  
Veronica M. Beretta ◽  
Israr Ud Din ◽  
Elia Lacchini ◽  
Lisa Van den Broeck ◽  
...  
Keyword(s):  
Leucine Zipper ◽  
Important Determinant ◽  
Rna Seq ◽  
Loss Of Function ◽  
Key Factors ◽  
Temporal Expression ◽  
Inflorescence Development ◽  
Gene Regulatory ◽  
Spatio Temporal ◽  
Number Of Branches

The architecture of the rice inflorescence is an important determinant of seed yield. The length of the inflorescence and the number of branches are among the key factors determining the amount of spikelets, and thus seeds, that will develop. Especially the timing of the identity transition from indeterminate branch meristem to determinate spikelet meristem regulates the complexity of the inflorescence. In this context, the ALOG gene TAWAWA1 (TAW1) has been shown to delay the transition to determinate spikelet development in rice. Recently, by combining precise laser microdissection of inflorescence meristems with RNA-seq we observed that two ALOG genes, Oryza sativa OsG1-like 1 (OsG1L1) and OsG1L2, have an expression profile similar to TAW1. Here we report that osg1l1 and osg1l2 loss-of-function CRISPR mutants have similar phenotypes as the taw1 mutant, suggesting that these genes might act on related pathways during inflorescence development. Transcriptome analysis of the osg1l2 mutant suggested interactions of OsG1L2 with other known inflorescence architecture regulators and the datasets were also used for the construction of a gene regulatory network (GRN) proposing interactions between genes potentially involved in controlling inflorescence development in rice. The spatio-temporal expression profiling and phenotypical analysis of CRISPR loss-of-function mutants of the homeodomain-leucine zipper transcription factor gene OsHOX14 suggest that the proposed GRN indeed serves as a valuable resource for the identification of new players involved in rice inflorescence development.

scholarly journals Genomic landscapes of non-coding RNAs regulating VEGFA and VEGFC expression in endothelial cells

2021 ◽  
Author(s):  
Isidore Mushimiyimana ◽  
Vanesa Tomas Bosch ◽  
Henri Niskanen ◽  
Nicholas Downes ◽  
Pierre Moreau ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Growth Factors ◽  
Vascular Endothelial ◽  
Rna Seq ◽  
Functional Roles ◽  
Genome Wide ◽  
Non Coding Rnas ◽  
Endothelial Growth Factors ◽  
Regulatory Landscape

Vascular endothelial growth factors (VEGFs) are best known as key regulators of angiogenesis and lymphangiogenesis. Although VEGFs have been promising therapeutic targets for various cardiovascular related diseases, their regulatory landscape in endothelial cells remains elusive. Several studies have highlighted the involvement of non-coding RNAs (ncRNAs) in the modulation of VEGF expression. In this study, we investigated the role of two classes of non-coding RNAs, long ncRNA (lncRNA) and enhancer RNAs (eRNAs), in the transcriptional regulation of VEGFA and VEGFC. By integrating genome-wide global run-on (GRO-seq) and Hi-C data, we identified putative lncRNAs and eRNAs associated with VEGFA and VEGFC genes in endothelial cells. A subset of the identified putative enhancers demonstrated regulatory activity in a reporter assay. Importantly, we demonstrate that deletion of enhancers and lncRNAs by CRISPR/Cas9 promoted significant changes in VEGFA and VEGFC expression. RNA-seq data from lncRNA deletions showed downstream factors implicated in VEGFA and VEGFC linked pathways, such as angiogenesis and lymphangiogenesis, suggesting functional roles for these lncRNAs. Our study uncovers novel lncRNAs and eRNAs regulating VEGFA and VEGFC that can be targeted to modulate the expression of these important molecules in endothelial cells.

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