scholarly journals Role of Alternative Splicing in Sex Determination in Vertebrates

2021 ◽  
pp. 1-11
Author(s):  
Isabel Gómez-Redondo ◽  
Benjamín Planells ◽  
Paula Navarrete ◽  
Alfonso Gutiérrez-Adán
Keyword(s):  
Alternative Splicing ◽  
Sex Determination ◽  
Transcription Initiation ◽  
Time Window ◽  
Gonad Development ◽  
Reproductive Organ ◽  
Mrna Splicing ◽  
Transcriptional Level ◽  
Splicing Regulators

During the process of sex determination, a germ-cell-containing undifferentiated gonad is converted into either a male or a female reproductive organ. Both the composition of sex chromosomes and the environment determine sex in vertebrates. It is assumed that transcription level regulation drives this cascade of mechanisms; however, transcription factors can alter gene expression beyond transcription initiation by controlling pre-mRNA splicing and thereby mRNA isoform production. Using the key time window in sex determination and gonad development in mice, it has been reported that new non-transcriptional events, such as alternative splicing, could play a key role in sex determination in mammals. We know the role of key regulatory factors, like WT1(+/–KTS) or FGFR2(b/c) in pre-mRNA splicing and sex determination, indicating that important steps in the vertebrate sex determination process probably operate at a post-transcriptional level. Here, we discuss the role of pre-mRNA splicing regulators in sex determination in vertebrates, focusing on the new RNA-seq data reported from mice fetal gonadal transcriptome.

scholarly journals hnRNPH1 recruits PTBP2 and SRSF3 to cooperatively modulate alternative pre-mRNA splicing in germ cells and is essential for spermatogenesis and oogenesis

2021 ◽  
Author(s):  
Shuiqiao Yuan ◽  
Shenglei Feng ◽  
Jinmei Li ◽  
Hui Wen ◽  
Kuan Liu ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Germ Cell ◽  
Germ Cells ◽  
Rna Binding ◽  
Cell Development ◽  
Mrna Splicing ◽  
Conditional Knockout ◽  
Cell Junction ◽  
Germ Cell Development ◽  
Splicing Regulators

Abstract Coordinated regulation of alternative pre-mRNA splicing is essential for germ cell development. However, the molecular mechanism underlying that control alternative mRNA expression during germ cell development remains poorly understood. Herein, we showed that hnRNPH1, an RNA-binding protein, is highly expressed in the reproductive system and localized in the chromosomes of meiotic cells but excluded from the XY body in pachytene spermatocytes and recruits the splicing regulators PTBP2 and SRSF3 and cooperatively regulates the alternative splicing of the critical genes that are required for spermatogenesis. Conditional knockout Hnrnph1 in spermatogenic cells caused many abnormal splicing events that affect genes related to meiosis and communication between germ cells and Sertoli cells, characterized by asynapsis of chromosomes and impairment of germ-Sertoli communications, ultimately leading to male sterility. We further showed that hnRNPH1 could directly bind to SPO11 and recruit the splicing regulators PTBP2 and SRSF3 to regulate the alternative splicing of the target genes cooperatively. Strikingly, Hnrnph1 germline-specific mutant female mice were also infertile, and Hnrnph1-deficient oocytes exhibited a similar defective synapsis and cell-cell junction as shown in Hnrnph1-deficient male germ cells. Collectively, our data reveal an essential role for hnRNPH1 in regulating pre-mRNA splicing during spermatogenesis and oogenesis and support a molecular model whereby hnRNPH1 governs a network of alternative splicing events in germ cells via recruiting PTBP2 and SRSF3.

Abstract 124: Fetal-Like RNA Splicing Remodeling in Failing Heart Revealed by Total Transcriptome Analysis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Chen Gao ◽  
Vincent Ren ◽  
Grace (Xinshu) Xiao ◽  
Jaunian Chen ◽  
Yibin Wang
Keyword(s):  
Alternative Splicing ◽  
Rna Splicing ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Expression Profiles ◽  
Mrna Splicing ◽  
Mouse Heart ◽  
Failing Heart ◽  
Splicing Regulators ◽  
A Genome

The complexity of transcriptome and proteome is contributed by alternative splicing of mRNA. Altered mRNA splicing is also implicated in many human diseases including cancer. However, little knowledge is available about the scope of alternative splicing at whole genome level in heart diseases and even less about the mechanisms underlying the regulation of mRNA splicing in response to pathological injury in heart. Using a genome-wide RNA-Seq analysis, we have identified global alternative splicing changes associated with both development and pathological remodeling in mouse heart. Most significantly, the alternative RNA splicing events observed in failing heart mimicked the splicing profile in fetal hearts, suggesting a fetal like RNA splicing remodeling in failing hearts. After examining the expression profiles of splicing regulators in neonatal, normal adult, and failing adult hearts, Fox-1 was identified as one to be significantly down regulated in the failing and fetal hearts. Morpholino mediated Fox-1 knock-down in zebrafish embryos led to lethal phenotype associated with impaired cardiac development and function. This phenotype could be rescued by re-expressing both zebrafish and mouse Fox1 gene. Therefore, our established functional significance of Fox1 mediated RNA alternative splicing serves as a key molecular player in transcriptome remodeling during cardiac development and pathology.

Histone modifications influence skipped exons inclusion

2017 ◽  
Vol 15 (01) ◽  
pp. 1750003 ◽  
Author(s):  
Yue Hou ◽  
Huan Huang ◽  
Wenqiao Hu ◽  
Hongde Liu ◽  
Xiao Sun
Keyword(s):  
Rna Polymerase Ii ◽  
Cell Lines ◽  
Histone Modifications ◽  
Transcription Initiation ◽  
Nucleosome Occupancy ◽  
Effector Proteins ◽  
Mrna Splicing ◽  
Genomic Complexity ◽  
Flanking Regions

Alternative splicing (AS), by which individual genes can produce multiple mRNA, associates with genomic complexity, disease, and development. Histone modifications show important roles in both transcription initiation and mRNA splicing. Here, we intended to find the link between AS and histone modifications in flanking regions through analyzing publicly available data in two human cell lines, GM12878 and K562 cell lines. According to exon inclusion levels, exons were classified into three types, included skipped exons, excluded skipped exons and expressed constitutive exons. We revealed that the inclusion levels of skipped exons (SEs) were negatively correlated with the enrichment of active histone marks in SEs, indicating a role of histone modifications in AS. We also found that active histone modifications were enriched in the upstream exons of SEs, especially around 5[Formula: see text] splicing sites. We inferred that the histone modifications around the 5[Formula: see text] splicing sites in upstream exon of the SEs could help RNA Polymerase II complex to recruit the effector proteins and facilitate AS. It was indicated that nucleosome occupancy had little influence on the inclusion levels of SEs. At last, we proposed an integrated model that describe how histone modifications affected the pre-mRNA splicing.

scholarly journals Integrative Deep Models for Alternative Splicing

2017 ◽  
Author(s):  
Anupama Jha ◽  
Matthew R. Gazzara ◽  
Yoseph Barash
Keyword(s):  
Alternative Splicing ◽  
Missing Values ◽  
Probabilistic Models ◽  
Genomic Sequence ◽  
Target Function ◽  
Detailed Comparison ◽  
Modeling Framework ◽  
Sequencing Technologies ◽  
Splicing Regulators

AbstractAdvancements in sequencing technologies have highlighted the role of alternative splicing (AS) in increasing transcriptome complexity. This role of AS, combined with the relation of aberrant splicing to malignant states, motivated two streams of research, experimental and computational. The First involves a myriad of techniques such as RNA-Seq and CLIP-Seq to identify splicing regulators and their putative targets. The second involves probabilistic models, also known as splicing codes, which infer regulatory mechanisms and predict splicing outcome directly from genomic sequence. To date, these models have utilized only expression data. In this work we address two related challenges: Can we improve on previous models for AS outcome prediction and can we integrate additional sources of data to improve predictions for AS regulatory factors. We perform a detailed comparison of two previous modeling approaches, Bayesian and Deep Neural networks, dissecting the confounding effects of datasets and target functions. We then develop a new target function for AS prediction and show that it significantly improves model accuracy. Next, we develop a modeling framework to incorporate CLIP-Seq, knockdown and over-expression experiments, which are inherently noisy and suffer from missing values. Using several datasets involving key splice factors in mouse brain, muscle and heart we demonstrate both the prediction improvements and biological insights offered by our new models. Overall, the framework we propose offers a scalable integrative solution to improve splicing code modeling as vast amounts of relevant genomic data become available.Availability: code and data will be available on Github following publication.

scholarly journals The germline-specific region of the sea lamprey genome plays a key role in spermatogenesis

2021 ◽  
Author(s):  
Tamanna Yasmin ◽  
Phil Grayson ◽  
Margaret F. Docker ◽  
Sara V. Good
Keyword(s):  
Sex Determination ◽  
Genome Rearrangement ◽  
De Novo ◽  
Sequence Data ◽  
Gonad Development ◽  
Sea Lamprey ◽  
Specific Region ◽  
A Genome ◽  
Reproductive Processes

The sea lamprey genome undergoes programmed genome rearrangement (PGR) in which ~20% is jettisoned from somatic cells soon after fertilization. Although the role of PGR in embryonic development has been studied, the role of the germline-specific region (GSR) in gonad development is unknown. We analysed RNA-sequence data from 28 sea lamprey gonads sampled across life-history stages, generated a genome-guided de novo superTransciptome with annotations, and identified genes in the GSR. We found that the 638 genes in the GSR are enriched for reproductive processes, exhibit 36x greater odds of being expressed in testes than ovaries, show little evidence of conserved synteny with other chordates, and most have putative paralogues in the GSR and/or somatic genomes. Further, several of these genes play known roles in sex determination and differentiation in other vertebrates. We conclude that the GSR of sea lamprey plays an important role in testicular differentiation and potentially sex determination.

scholarly journals Bioinformatics challenges and perspectives when studying the effect of epigenetic modifications on alternative splicing

2018 ◽  
Vol 373 (1748) ◽  
pp. 20170073 ◽  
Author(s):  
Clare Pacini ◽  
Magdalena J. Koziol
Keyword(s):  
Alternative Splicing ◽  
Chemical Biology ◽  
Epigenetic Modifications ◽  
Mrna Splicing ◽  
Epigenetic Changes ◽  
Epigenetic Marks

It is widely known that epigenetic modifications are important in regulating transcription, but several have also been reported in alternative splicing. The regulation of pre-mRNA splicing is important to explain proteomic diversity and the misregulation of splicing has been implicated in many diseases. Here, we give a brief overview of the role of epigenetics in alternative splicing and disease. We then discuss the bioinformatics methods that can be used to model interactions between epigenetic marks and regulators of splicing. These models can be used to identify alternative splicing and epigenetic changes across different phenotypes. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.

55 Identification of microRNAs associated with sex determination in bovine amniotic fluid and maternal blood plasma

2020 ◽  
Vol 32 (2) ◽  
pp. 153 ◽  
Author(s):  
J. M. Sánchez ◽  
I. Gómez-Redondo ◽  
J. A. Browne ◽  
B. Planells ◽  
A. Gutiérrez-Adán ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Sex Determination ◽  
Blood Plasma ◽  
Sex Chromosome ◽  
Gonad Development ◽  
Maternal Blood ◽  
Biological Processes ◽  
Female Embryo ◽  
Male Embryo

In most eutherian mammals, sex determination is the process through which a bipotential gonad (also known as genital ridges) develops into a testis or ovary depending on the sex chromosome content of the embryo, specifically by the presence of the SRY/Sry gene (sex-determining region of the Y chromosome). MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression and are involved in diverse functional roles including development, differentiation, apoptosis, and immunity. We hypothesised that the expression of miRNAs in amniotic fluid (AF) and maternal blood plasma (MP) would be affected by the sex of the embryo around the time of sex determination. Amniotic fluid and MP were collected from 6 crossbred beef pregnant heifers (3 carrying a single male and 3 carrying a single female embryo) following slaughter on Day 39 (when the peak of SRY expression occurs in cattle). All heifers had been synchronized and inseminated with semen from the same beef bull. A total of 12 samples (6 AF and 6 MP) were profiled using the miRCURY LNA miRNA Serum/Plasma Focus PCR Panel (Qiagen; 179 assays targeting relevant miRNAs). Data were analysed by GeneGlobe Data Analysis Center (Qiagen). A threshold cycle cut-off of 35 was applied and data were analysed using an unpaired t-test. Gene ontology enrichment analysis was performed using the WebGestaltR package to explore the possible functions of differentially expressed (DE) miRNAs. In this study, DE miRNAs were identified in male vs. female AF (n=5; 3 upregulated and 2 downregulated; P<0.05) and MP (n=57; 54 upregulated and 3 downregulated; P<0.05). Although no enrichment was detected for DE miRNAs in AF (in either sex) or in MP in heifers carrying a female embryo, 37 biological processes were enriched by DE miRNAs in MP of heifers carrying a male embryo (false discovery rate<0.05). Interestingly, the top five most enriched biological processes were male gonad development, development of primary male sexual characteristics, signal transduction in absence of ligand, actomyosin structure organisation, and male sex differentiation, suggesting a potential role of these miRNAs in reproductive traits. Results from this study highlight unique aspects of sex determination in cattle such as the role of miRNAs in gonad development. Moreover, although it is well known that AF provides a protective space around the developing embryo/fetus that allows its movement and growth; here we provide evidence suggesting that its components may play important roles in fetal development. Finally, miRNAs in MP may offer new opportunities to investigate biomarkers for early prediction of embryo/fetal sex in commercial practice. This research was supported by the Science Foundation Ireland (13/IA/1983) and the European Union H2020 Marie Sklodowska-Curie Innovative Training Network project Biology and Technology of Reproductive Health - REP-BIOTECH - 675526.

scholarly journals Oncogenic Alternative Splicing Switches: Role in Cancer Progression and Prospects for Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Serena Bonomi ◽  
Stefania Gallo ◽  
Morena Catillo ◽  
Daniela Pignataro ◽  
Giuseppe Biamonti ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Progression ◽  
Cancer Treatments ◽  
Splicing Regulators ◽  
Transcriptional Regulatory Mechanism ◽  
Transcriptional Regulatory ◽  
Anti Cancer ◽  
Alternatively Spliced ◽  
Splicing Isoforms

Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.

scholarly journals Blood Relatives: Splicing Mechanisms underlying Erythropoiesis in Health and Disease

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1364 ◽  
Author(s):  
Kirsten A. Reimer ◽  
Karla M. Neugebauer
Keyword(s):  
Alternative Splicing ◽  
Gene Editing ◽  
Intron Retention ◽  
Mrna Splicing ◽  
Globin Mrna ◽  
Disease Treatment ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Health And Disease

During erythropoiesis, hematopoietic stem and progenitor cells transition to erythroblasts en route to terminal differentiation into enucleated red blood cells. Transcriptome-wide changes underlie distinct morphological and functional characteristics at each cell division during this process. Many studies of gene expression have historically been carried out in erythroblasts, and the biogenesis of β-globin mRNA—the most highly expressed transcript in erythroblasts—was the focus of many seminal studies on the mechanisms of pre-mRNA splicing. We now understand that pre-mRNA splicing plays an important role in shaping the transcriptome of developing erythroblasts. Recent advances have provided insight into the role of alternative splicing and intron retention as important regulatory mechanisms of erythropoiesis. However, dysregulation of splicing during erythropoiesis is also a cause of several hematological diseases, including β-thalassemia and myelodysplastic syndromes. With a growing understanding of the role that splicing plays in these diseases, we are well poised to develop gene-editing treatments. In this review, we focus on changes in the developing erythroblast transcriptome caused by alternative splicing, the molecular basis of splicing-related blood diseases, and therapeutic advances in disease treatment using CRISPR/Cas9 gene editing.

scholarly journals Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD

2021 ◽  
Author(s):  
Kathryn R. Bowles ◽  
Derian A. Pugh ◽  
Laura-Maria Oja ◽  
Benjamin M. Jadow ◽  
Kurt Farrell ◽  
...  
Keyword(s):  
Temporal Cortex ◽  
Mrna Splicing ◽  
Human Brain Tissue ◽  
Gene Encoding ◽  
Exon 2 ◽  
Combinatorial Regulation ◽  
Splicing Regulators ◽  
Microtubule Binding Domain ◽  
Exon 10

ABSTRACTUnderstanding regulation of MAPT splicing is important to the etiology of many nerurodegenerative diseases, including Alzheimer disease (AD) and progressive supranuclear palsy (PSP), in which different tau isoforms accumulate in pathologic inclusions. MAPT, the gene encoding the tau protein, undergoes complex alternative pre-mRNA splicing to generate six isoforms. Tauopathies can be categorized by the presence of tau aggregates containing either 3 (3R) or 4 (4R) microtubule binding domain repeats (determined by inclusion/exclusion of exon 10), but the role of the N terminal domain of the protein, determined by inclusion/exclusion of exons 2 and 3 has been less well studied. Using an unbiased correlational screen in human brain tissue, we observed coordination of MAPT exons 2 and 10 splicing. Expression of exon 2 splicing regulators and subsequently exon 2 inclusion are differentially disrupted in PSP and AD brain, resulting in the accumulation of 1N4R isoforms in PSP and 0N isoforms in AD temporal cortex. Furthermore, we identified different N-terminal isoforms of tau present in neurofibrillary tangles, dystrophic neurites and tufted astrocytes, indicating a role for differential N-terminal splicing in the development of disparate tau neuropathologies. We conclude that N-terminal splicing and combinatorial regulation with exon 10 inclusion/exclusion is likely to be important to our understanding of tauopathies.

Sign in / Sign up

Export Citation Format

Share Document