scholarly journals Insulinlike Growth Factor 1 Gene Variation in Vertebrates

Endocrinology ◽  
2018 ◽  
Vol 159 (6) ◽  
pp. 2288-2305 ◽  
Author(s):  
Peter Rotwein
Keyword(s):  
Evolutionary History ◽  
Somatic Growth ◽  
Regulatory Elements ◽  
Single Chain ◽  
Exon 2 ◽  
Gene Variation ◽  
Large Intron ◽  
Different Types ◽  
Transcriptional Pathway ◽  
Igf1 Expression

Abstract IGF1—a small, single-chain, secreted peptide in mammals—is essential for normal somatic growth and is involved in a variety of other physiological and pathophysiological processes. IGF1 expression appears to be controlled by several different signaling mechanisms in mammals, with GH playing a key role by activating an inducible transcriptional pathway via the Jak2 protein kinase and the Stat5b transcription factor. Here, to understand aspects of Igf1 gene regulation over a substantially longer timeline than is discernible in mammals, Igf1 genes have been examined in 21 different nonmammalian vertebrates representing five different classes and ranging over ∼500 million years of evolutionary history. Parts of vertebrate Igf1 genes resemble components found in mammals. Conserved exons encoding the mature IGF1 protein are detected in all 21 species studied and are separated by a large intron, as seen in mammals; the single promoter contains putative regulatory elements that are similar to those functionally mapped in human IGF1 promoter 1. In contrast, GH-activated Stat5b-binding enhancers found in mammalian IGF1 loci are completely absent, there is no homolog of promoter 2 or exon 2 in any nonmammalian vertebrate, and different types of “extra” exons not present in mammals are found in birds, reptiles, and teleosts. These data collectively define properties of Igf1 genes and IGF1 proteins that were likely present in the earliest vertebrates and support the contention that common structural and regulatory features in Igf1 genes have a long evolutionary history.

Subfunctionalization of Duplicate mitf Genes Associated With Differential Degeneration of Alternative Exons in Fish

Genetics ◽  
2002 ◽  
Vol 161 (1) ◽  
pp. 259-267 ◽  
Author(s):  
Joachim Altschmied ◽  
Jacqueline Delfgaauw ◽  
Brigitta Wilde ◽  
Jutta Duschl ◽  
Laurence Bouneau ◽  
...  
Keyword(s):  
Danio Rerio ◽  
Evolutionary History ◽  
Single Gene ◽  
Regulatory Elements ◽  
Fugu Rubripes ◽  
Gene Encoding ◽  
Tetraodon Nigroviridis ◽  
Mammalian Lineage ◽  
History Of ◽  
Fish Proteins

Abstract The microphthalmia-associated transcription factor (MITF) exists in at least four isoforms. These are generated in higher vertebrates using alternative 5′ exons and promoters from a single gene. Two separate genes (mitf-m and mitf-b), however, are present in different teleost fish species including the poeciliid Xiphophorus, the pufferfishes Fugu rubripes and Tetraodon nigroviridis, and the zebrafish Danio rerio. Fish proteins MITF-m and MITF-b correspond at both the structural and the expression levels to one particular bird/mammalian MITF isoform. In the teleost lineage subfunctionalization of mitf genes after duplication at least 100 million years ago is associated with the degeneration of alternative exons and, probably, regulatory elements and promoters. For example, a remnant of the first exon specific for MITF-m is detected within the pufferfish gene encoding MITF-b. Retracing the evolutionary history of mitf genes in vertebrates uncovered the differential recruitment of new introns specific for either the teleost or the bird/mammalian lineage.

scholarly journals Negative and Positive mRNA Splicing Elements Act Competitively To Regulate Human Immunodeficiency Virus Type 1 Vif Gene Expression

2008 ◽  
Vol 82 (8) ◽  
pp. 3921-3931 ◽  
Author(s):  
C. M. Exline ◽  
Z. Feng ◽  
C. M. Stoltzfus
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Regulatory Elements ◽  
Mrna Splicing ◽  
Viral Mrnas ◽  
Exon 2 ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Over 40 different human immunodeficiency virus type 1 (HIV-1) mRNAs are produced by alternative splicing of the primary HIV-1 RNA transcripts. In addition, approximately half of the viral RNA remains unspliced and is used as genomic RNA and as mRNA for the Gag and Pol gene products. Regulation of splicing at the HIV-1 3′ splice sites (3′ss) requires suboptimal polypyrimidine tracts, and positive or negative regulation occurs through the binding of cellular factors to cis-acting splicing regulatory elements. We have previously shown that splicing at HIV-1 3′ss A1, which produces single-spliced vif mRNA and promotes the inclusion of HIV exon 2 into both completely and incompletely spliced viral mRNAs, is increased by optimizing the 5′ splice site (5′ss) downstream of exon 2 (5′ss D2). Here we show that the mutations within 5′ss D2 that are predicted to lower or increase the affinity of the 5′ss for U1 snRNP result in reduced or increased Vif expression, respectively. Splicing at 5′ss D2 was not necessary for the effect of 5′ss D2 on Vif expression. In addition, we have found that mutations of the GGGG motif proximal to the 5′ss D2 increase exon 2 inclusion and Vif expression. Finally, we report the presence of a novel exonic splicing enhancer (ESE) element within the 5′-proximal region of exon 2 that facilitates both exon inclusion and Vif expression. This ESE binds specifically to the cellular SR protein SRp75. Our results suggest that the 5′ss D2, the proximal GGGG silencer, and the ESE act competitively to determine the level of vif mRNA splicing and Vif expression. We propose that these positive and negative splicing elements act together to allow the accumulation of vif mRNA and unspliced HIV-1 mRNA, compatible with optimal virus replication.

scholarly journals Fast skeletal muscle-specific expression of a quail troponin I gene in transgenic mice.

1988 ◽  
Vol 8 (12) ◽  
pp. 5072-5079 ◽  
Author(s):  
P L Hallauer ◽  
K E Hastings ◽  
A C Peterson
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Troponin I ◽  
Fiber Type ◽  
Regulatory Elements ◽  
Evolutionary Divergence ◽  
Mrna Levels ◽  
Fast Skeletal Muscle ◽  
Specific Expression ◽  
Exon 2

We have produced seven lines of transgenic mice carrying the quail gene encoding the fast skeletal muscle-specific isoform of troponin I (TnIf). The quail DNA included the entire TnIf gene, 530 base pairs of 5'-flanking DNA, and 1.5 kilobase pairs of 3'-flanking DNA. In all seven transgenic lines, normally initiated and processed quail TnIf mRNA was expressed in skeletal muscle, where it accumulated to levels comparable to that in quail muscle. Moreover, in the three lines tested, quail TnIf mRNA levels were manyfold higher in a fast skeletal muscle (gastrocnemius) than in a slow skeletal muscle (soleus). We conclude that the cellular mechanisms directing muscle fiber type-specific TnIf gene expression are mediated by cis-regulatory elements present on the introduced quail DNA fragment and that they control TnIf expression by affecting the accumulation of TnIf mRNA. These elements have been functionally conserved since the evolutionary divergence of birds and mammals, despite the major physiological and morphological differences existing between avian (tonic) and mammalian (twitch) slow muscles. In lines of transgenic mice carrying multiple tandemly repeated copies of the transgene, an aberrant quail TnIf transcript (differing from normal TnIf mRNA upstream of exon 2) also accumulated in certain tissues, particularly lung, brain, spleen, and heart tissues. However, this aberrant transcript was not detected in a transgenic line which carries only a single copy of the quail gene.

Molecular phylogeny of diploid Hordeum species and incongruence between chloroplast and nuclear datasets

Genome ◽  
2011 ◽  
Vol 54 (12) ◽  
pp. 986-992 ◽  
Author(s):  
Huan Wang ◽  
Dongfa Sun ◽  
Genlou Sun
Keyword(s):  
Evolutionary History ◽  
Nuclear Gene ◽  
Intergenic Spacer ◽  
Molecular Data ◽  
Genome Species ◽  
Different Types ◽  
History Of ◽  
Morphological And Molecular Data ◽  
Hordeum Species ◽  
Eurasian Species

The phylogeny of diploid Hordeum species has been studied using both chloroplast and nuclear gene sequences. However, the studies of different nuclear datasets of Hordeum species often arrived at similar conclusions, whereas the studies of different chloroplast DNA data generally resulted in inconsistent conclusions. Although the monophyly of the genus is well supported by both morphological and molecular data, the intrageneric phylogeny is still a matter of controversy. To better understand the evolutionary history of Hordeum species, two chloroplast gene loci (trnD-trnT intergenic spacer and rps16 gene) and one nuclear marker (thioreoxin-like gene (HTL)) were used to explore the phylogeny of Hordeum species. Two obviously different types of trnD-trnT sequences were observed, with an approximately 210 base pair difference between these two types: one for American species, another for Eurasian species. The trnD-trnT data generally separated the diploid Hordeum species into Eurasian and American clades, with the exception of Hordeum marinum subsp. gussoneanum. The rps16 data also grouped most American species together and suggested that Hordeum flexuosum has a different plastid type from the remaining American species. The nuclear gene HTL data clearly divided Hordeum species into two clades: the Xu + H genome clade and the Xa + I genome clade. Within clades, H genome species were well separated from the Xu species, and the I genome species were well separated from the Xa genome species. The incongruence between chloroplast and nuclear datasets was found and discussed.

scholarly journals Dissection of acute stimulus-inducible nucleosome remodeling in mammalian cells

2019 ◽  
Author(s):  
Federico Comoglio ◽  
Marta Simonatto ◽  
Sara Polletti ◽  
Xin Liu ◽  
Stephen T. Smale ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Regulatory Elements ◽  
Micrococcal Nuclease ◽  
Nucleosome Remodeling ◽  
Nucleosome Dynamics ◽  
Nucleosome Organization ◽  
Regulatory Information ◽  
Different Types ◽  
Genomic Regions ◽  
The Impact

ABSTRACTAccessibility of the genomic regulatory information is largely controlled by the nucleosome-organizing activity of transcription factors (TFs). Whereas stimulus-induced TFs bind to genomic regions that are maintained accessible by lineage-determining TFs, they also increase accessibility of thousands of cis-regulatory elements. Nucleosome remodeling events underlying such changes and their interplay with basal positioning are unknown. Here, we devised a novel quantitative framework discriminating different types of nucleosome remodeling events in micrococcal nuclease ChIP-seq datasets and used it to analyze nucleosome dynamics at stimulus-regulated cis-regulatory elements. At enhancers, remodeling preferentially affected poorly positioned nucleosomes while sparing well-positioned nucleosomes flanking the enhancer core, indicating that inducible TFs do not suffice to overrule basal nucleosomal organization maintained by lineage-determining TFs. Remodeling events appeared to be combinatorially driven by multiple TFs, with distinct TFs showing however different remodeling efficiencies. Overall, these data provide a systematic view of the impact of stimulation on nucleosome organization and genome accessibility in mammalian cells.

Evolutionarily Conserved Coupling of Transcription and Alternative Splicing in the Protein 4.1R and 4.1B Genes Regulates N-Terminal Protein Structure.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1664-1664
Author(s):  
Jeff Tan ◽  
Marilyn K. Parra ◽  
Narla Mohandas ◽  
John G. Conboy
Keyword(s):  
Alternative Splicing ◽  
Rna Processing ◽  
Regulatory Elements ◽  
Protein Isoforms ◽  
Tissue Type ◽  
Translation Initiation Site ◽  
Acceptor Site ◽  
Exon 2 ◽  
Evolutionarily Conserved ◽  
Protein 4.1R

Abstract The protein 4.1R gene is regulated by complex pre-mRNA processing events that facilitate the synthesis of protein isoforms with different structure, function, and subcellular localization in red cells and various nucleated cell types. One of these events involves the stage-specific activation of exon 16 inclusion in erythroblasts, which mechanically stabilizes the membrane skeleton by increasing the protein’s affinity for spectrin and actin. Some of the splicing factor proteins and RNA regulatory elements responsible for this tissue-specific alternative splicing event have been defined. Here we focus on another RNA processing event, in the 5′ end of the transcript that can affect the structure and function of the membrane binding domain of protein 4.1R. We have shown that 4.1R transcripts originating at three far upstream alternative promoters/first exons splice differentially to alternative acceptor sites in exon 2′/2 in a manner that suggests strict coupling between transcription and alternative splicing events. A precisely analogous gene organization and RNA processing pattern has also been shown to occur in the paralogous 4.1B gene. Now we demonstrate that this coupling is evolutionarily conserved among several vertebrate classes from fish to mammals. The 4.1R and 4.1B genes from fish, bird, amphibian, and mammal genomes exhibit shared features including alternative first exons and differential splice acceptors in exon 2. In all cases, the 5′-most exon (exon 1A) splices exclusively to a weaker internal acceptor site in exon 2, skipping a short sequence designated as exon 2′ (17-33nt). Conversely, alternative first exons 1B and/or 1C always splice to the stronger first acceptor site, retaining exon 2′. These correlations are independent of tissue type or species of origin. Since exon 2′ contains a translation initiation site, this regulated splicing event generate protein isoforms with distinct N-termini. We propose that these 4.1 genes represent a physiologically relevant model system for mechanistic analysis of transcription-coupled alternative splicing. We have recently constructed a 9kb “minigene” that successfully reproduces the differential splicing patterns of exons 1A and 1B to exon 2′/2 in transfected cells. This minigene will facilitate identification of the determinants that guide coupling. Current experiments are testing the importance for proper splicing of the transcriptional promoter, first exon sequences, length and sequence of the intron, and sequence of a conserved element within exon 2′. Ultimately these studies should provide new insights into the mechanisms of coupling between far upstream, transcription-related processes and downstream alternative splicing.

scholarly journals Getting into position: the catalytic mechanisms of protein ubiquitylation

2004 ◽  
Vol 379 (3) ◽  
pp. 513-525 ◽  
Author(s):  
Lori A. PASSMORE ◽  
David BARFORD
Keyword(s):  
Protein Interactions ◽  
Regulatory Elements ◽  
Substrate Selection ◽  
Protein Protein Interactions ◽  
Different Types ◽  
Catalytic Mechanisms ◽  
Cellular Pathways ◽  
Ubiquitin Conjugating Enzymes ◽  
Insight Into

The role of protein ubiquitylation in the control of diverse cellular pathways has recently gained widespread attention. Ubiquitylation not only directs the targeted destruction of tagged proteins by the 26 S proteasome, but it also modulates protein activities, protein–protein interactions and subcellular localization. An understanding of the components involved in protein ubiquitylation (E1s, E2s and E3s) is essential to understand how specificity and regulation are conferred upon these pathways. Much of what we know about the catalytic mechanisms of protein ubiquitylation comes from structural studies of the proteins involved in this process. Indeed, structures of ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) have provided insight into their mechanistic details. E3s (ubiquitin ligases) contain most of the substrate specificity and regulatory elements required for protein ubiquitylation. Although several E3 structures are available, the specific mechanistic role of E3s is still unclear. This review will discuss the different types of ubiquitin signals and how they are generated. Recent advances in the field of protein ubiquitylation will be examined, including the mechanisms of E1, E2 and E3. In particular, we discuss the complexity of molecular recognition required to impose selectivity on substrate selection and topology of poly-ubiquitin chains.

scholarly journals Alternative splicing is a developmental switch for hTERT expression

2020 ◽  
Author(s):  
Alex Penev ◽  
Andrew Bazley ◽  
Michael Shen ◽  
Jef D. Boeke ◽  
Sharon A. Savage ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcriptional Control ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
Telomerase Activity ◽  
Dyskeratosis Congenita ◽  
Blastocyst Stage ◽  
Human Escs ◽  
Exon 2 ◽  
Telomerase Regulation

High telomerase activity is restricted to the blastocyst stage of embryonic development when telomere length is reset, and is characteristic of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, the pathways involved in telomerase regulation as a function of pluripotency remain unknown. To explore hTERT transcriptional control, we compare genome-wide interactions (4C-seq) and chromatin accessibility (ATAC-seq) between human ESCs and epithelial cells and identify several putative hTERT cis-regulatory elements. CRISPR/Cas9-mediated deletion of candidate elements in ESCs reduces the levels of hTERT mRNA but does not abolish telomerase expression, thus implicating post-transcriptional processes in telomerase regulation. In agreement with this hypothesis, we find an hTERT splice variant lacking exon-2 and prone to degradation, to be enriched in differentiated cells but absent from ESCs. In addition, we show that forced retention of exon-2 prevents telomerase silencing during differentiation. Lastly, we highlight a role for the splicing co-factor SON in hTERT exon-2 inclusion and identify a SON mutation in a Dyskeratosis congenita patient with short telomeres and decreased telomerase activity. Altogether, our data uncover a novel alternative splice switch that is critical for telomerase activity during development.

scholarly journals Evolutionary history of the MTG gene family in vertebrates

2019 ◽  
Vol 64 (4) ◽  
pp. 391-402
Author(s):  
A. I. Kavaleuskaya ◽  
T. V. Ramanouskaya
Keyword(s):  
Gene Family ◽  
Evolutionary History ◽  
Protein Sequences ◽  
Stem Cell Differentiation ◽  
Gene Products ◽  
Functional Diversification ◽  
Rates Of Evolution ◽  
Different Types ◽  
History Of ◽  
Transcriptional Corepressors

The highly conserved MTG gene family includes three homologs in vertebrates (MTG8, MTGR1, MTG16) encoding transcriptional corepressors, which are important in haemopoiesis, neurogenesis and epithelial stem cell differentiation. These genes are of particular interest because they are involved in translocations, associated with different types of cancer. Looking at how this gene family evolved might provide insights into history of its structural and functional diversification. We have performed a phylogenetic analysis of MTG nucleotide and protein sequences to examine the evolutionary events. The domain organization of MTG gene products was clarified, the mechanism of appearance of the first MTG gene was revealed and the ancestor taxon was determined. Also the mechanism of MTG gene family emergence was established. In addition, analysis of the rates of evolution acting on individual domains was made, and conservative positions within each gene of MTG family were determined.

scholarly journals High-throughput mutagenesis identifies mutations and RNA binding proteins controlling CD19 splicing and CART-19 therapy resistance

2021 ◽  
Author(s):  
Mariela Cortés-López ◽  
Laura Schulz ◽  
Mihaela Enculescu ◽  
Claudia Paret ◽  
Bea Spiekermann ◽  
...  
Keyword(s):  
High Throughput ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Single Point ◽  
Point Mutations ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Splice Isoforms ◽  
Exon 2

During CART-19 immunotherapy for B-cell acute lymphoblastic leukaemia (B-ALL), many patients relapse due to loss of the cognate CD19 epitope. Since epitope loss can be caused by aberrant CD19 exon 2 processing, we herein investigate the regulatory code that controls CD19 splicing. We combine high-throughput mutagenesis with mathematical modelling to quantitatively disentangle the effects of all mutations in the region comprising CD19 exons 1-3. Thereupon, we identify ~200 single point mutations that alter CD19 splicing and thus could predispose B-ALL patients to CART-19 resistance. Furthermore, we report almost 100 previously unknown splice isoforms that emerge from cryptic splice sites and likely encode non-functional CD19 proteins. We further identify cis-regulatory elements and trans-acting RNA-binding proteins that control CD19 splicing (e.g., PTBP1 and SF3B4) and validate that loss of these factors leads to enhanced CD19 mis-splicing. Our dataset represents a comprehensive resource for potential prognostic factors predicting success of CART-19 therapy.

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