scholarly journals Ectopic expression of a maize gene is induced by Composite Insertions generated through Alternative Transposition

2020 ◽  
Author(s):  
Weijia Su ◽  
Tao Zuo ◽  
Thomas Peterson
Keyword(s):  
Gene Expression ◽  
Transposable Elements ◽  
Dna Sequences ◽  
Methylation Status ◽  
Ectopic Expression ◽  
Regulatory Elements ◽  
Genome Rearrangements ◽  
Transcriptional Enhancer ◽  
Controlling Elements ◽  
Alternative Transposition

AbstractTransposable elements (TEs) are DNA sequences that can mobilize and proliferate throughout eukaryotic genomes. Previous studies have shown that in plant genomes, TEs can influence gene expression in various ways such as inserting in introns or exons to alter transcript structure and content, and providing novel promoters and regulatory elements to generate new regulatory patterns. Furthermore, TEs can also regulate gene expression at the epigenetic level by modifying chromatin structure, changing DNA methylation status and generating small RNAs. In this study, we demonstrated that Ac/fAc transposable elements are able to induce ectopic gene expression by duplicating and shuffling enhancer elements. Ac/fAc elements belong to the hAT family of Class II TEs. They can undergo standard transposition events, which involve the two termini of a single transposon, or alternative transposition events which involve the termini of two different, nearby elements. Our previous studies have shown that alternative transposition can generate various genome rearrangements such as deletions, duplications, inversions, translocations and Composite Insertions (CIs). We identified over 50 independent cases of CIs generated by Ac/fAc alternative transposition and analyzed 10 of them in detail. We show that these CIs induced ectopic expression of the maize pericarp color 2 (p2) gene, which encodes a Myb-related protein. All the CIs analyzed contain sequences including a transcriptional enhancer derived from the nearby p1 gene, suggesting that the CI-induced activation of p2 is effected by mobilization of the p1 enhancer. This is further supported by analysis of a mutant in which the CI is excised and p2 expression is lost. These results show that alternative transposition events are not only able to induce genome rearrangements, but also generate Composite Insertions that can control gene expression.SummaryWhen Barbara McClintock originally identified and characterized Transposable Elements (TEs) in maize, she termed them “Controlling Elements” due to their effects on gene expression. Here we show that maize Ac/Ds TEs can acquire a genomic enhancer and generate Composite Insertions (CIs) that activate expression of a nearby gene. CIs are structurally variable elements that include TE termini enclosing sequences from an original donor locus, and are formed when the termini of two nearby TEs transpose during S phase from a replicated to unreplicated site. In this way, TEs may acquire genomic enhancers to generate Controlling Elements as described by McClintock.

scholarly journals Ectopic Expression of a Maize Gene Is Induced by Composite Insertions Generated Through Alternative Transposition

Genetics ◽  
2020 ◽  
Vol 216 (4) ◽  
pp. 1039-1049
Author(s):  
Weijia Su ◽  
Tao Zuo ◽  
Thomas Peterson
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Methylation Status ◽  
Ectopic Expression ◽  
Regulatory Elements ◽  
Genome Rearrangements ◽  
Transcriptional Enhancer ◽  
Pericarp Color ◽  
Transcript Structure ◽  
Alternative Transposition

Transposable elements (TEs) are DNA sequences that can mobilize and proliferate throughout eukaryotic genomes. Previous studies have shown that in plant genomes, TEs can influence gene expression in various ways, such as inserting in introns or exons to alter transcript structure and content, and providing novel promoters and regulatory elements to generate new regulatory patterns. Furthermore, TEs can also regulate gene expression at the epigenetic level by modifying chromatin structure, changing DNA methylation status, and generating small RNAs. In this study, we demonstrated that Ac/fractured Ac (fAc) TEs are able to induce ectopic gene expression by duplicating and shuffling enhancer elements. Ac/fAc elements belong to the hAT family of class II TEs. They can undergo standard transposition events, which involve the two termini of a single transposon, or alternative transposition events that involve the termini of two different nearby elements. Our previous studies have shown that alternative transposition can generate various genome rearrangements such as deletions, duplications, inversions, translocations, and composite insertions (CIs). We identified >50 independent cases of CIs generated by Ac/fAc alternative transposition and analyzed 10 of them in detail. We show that these CIs induced ectopic expression of the maize pericarp color 2 (p2) gene, which encodes a Myb-related protein. All the CIs analyzed contain sequences including a transcriptional enhancer derived from the nearby p1 gene, suggesting that the CI-induced activation of p2 is affected by mobilization of the p1 enhancer. This is further supported by analysis of a mutant in which the CI is excised and p2 expression is lost. These results show that alternative transposition events are not only able to induce genome rearrangements, but also generate CIs that can control gene expression.

scholarly journals Evolution of mouse circadian enhancers from transposable elements

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Julius Judd ◽  
Hayley Sanderson ◽  
Cédric Feschotte
Keyword(s):  
Gene Expression ◽  
Transposable Elements ◽  
Binding Sites ◽  
Mouse Liver ◽  
Integration Site ◽  
Point Mutations ◽  
Regulatory Elements ◽  
Circadian Gene ◽  
Binding Motifs ◽  
Reporter Assays

Abstract Background Transposable elements are increasingly recognized as a source of cis-regulatory variation. Previous studies have revealed that transposons are often bound by transcription factors and some have been co-opted into functional enhancers regulating host gene expression. However, the process by which transposons mature into complex regulatory elements, like enhancers, remains poorly understood. To investigate this process, we examined the contribution of transposons to the cis-regulatory network controlling circadian gene expression in the mouse liver, a well-characterized network serving an important physiological function. Results ChIP-seq analyses reveal that transposons and other repeats contribute ~ 14% of the binding sites for core circadian regulators (CRs) including BMAL1, CLOCK, PER1/2, and CRY1/2, in the mouse liver. RSINE1, an abundant murine-specific SINE, is the only transposon family enriched for CR binding sites across all datasets. Sequence analyses and reporter assays reveal that the circadian regulatory activity of RSINE1 stems from the presence of imperfect CR binding motifs in the ancestral RSINE1 sequence. These motifs matured into canonical motifs through point mutations after transposition. Furthermore, maturation occurred preferentially within elements inserted in the proximity of ancestral CR binding sites. RSINE1 also acquired motifs that recruit nuclear receptors known to cooperate with CRs to regulate circadian gene expression specifically in the liver. Conclusions Our results suggest that the birth of enhancers from transposons is predicated both by the sequence of the transposon and by the cis-regulatory landscape surrounding their genomic integration site.

scholarly journals Gene Expression Networks in the Drosophila Genetic Reference Panel

2019 ◽  
Author(s):  
Logan J. Everett ◽  
Wen Huang ◽  
Shanshan Zhou ◽  
Mary Anna Carbone ◽  
Richard F. Lyman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transposable Elements ◽  
Dna Sequences ◽  
Quantitative Trait ◽  
Regulatory Networks ◽  
Target Genes ◽  
Reference Panel ◽  
Modern Biology ◽  
Specific Expression ◽  
Drosophila Genetic Reference Panel

SummaryA major challenge in modern biology is to understand how naturally occurring variation in DNA sequences affects complex organismal traits through networks of intermediate molecular phenotypes. Here, we performed deep RNA sequencing of 200 Drosophila Genetic Reference Panel inbred lines with complete genome sequences, and mapped expression quantitative trait loci for annotated genes, novel transcribed regions (most of which are long noncoding RNAs), transposable elements and microbial species. We identified host variants that affect expression of transposable elements, independent of their copy number, as well as microbiome composition. We constructed sex-specific expression quantitative trait locus regulatory networks. These networks are enriched for novel transcribed regions and target genes in heterochromatin and euchromatic regions of reduced recombination, and genes regulating transposable element expression. This study provides new insights regarding the role of natural genetic variation in regulating gene expression and generates testable hypotheses for future functional analyses.

Mammalian genome evolution as a result of epigenetic regulation of transposable elements

2014 ◽  
Vol 5 (3) ◽  
pp. 183-194 ◽  
Author(s):  
Reuben M. Buckley ◽  
David L. Adelson
Keyword(s):  
Gene Expression ◽  
Transposable Elements ◽  
Epigenetic Regulation ◽  
Dna Sequences ◽  
Defense Mechanisms ◽  
Regulatory Networks ◽  
Regulation Of Gene Expression ◽  
Epigenetic Marks ◽  
Rna Molecules ◽  
Mammalian Genomes

AbstractTransposable elements (TEs) make up a large proportion of mammalian genomes and are a strong evolutionary force capable of rewiring regulatory networks and causing genome rearrangements. Additionally, there are many eukaryotic epigenetic defense mechanisms able to transcriptionally silence TEs. Furthermore, small RNA molecules that target TE DNA sequences often mediate these epigenetic defense mechanisms. As a result, epigenetic marks associated with TE silencing can be reestablished after epigenetic reprogramming – an event during the mammalian life cycle that results in widespread loss of parental epigenetic marks. Furthermore, targeted epigenetic marks associated with TE silencing may have an impact on nearby gene expression. Therefore, TEs may have driven species evolution via their ability to heritably alter the epigenetic regulation of gene expression in mammals.

scholarly journals Rearrangement of upstream regulatory elements leads to ectopic expression of the Drosophila mulleri Adh-2 gene.

Genetics ◽  
1992 ◽  
Vol 132 (4) ◽  
pp. 1071-1079
Author(s):  
D Falb ◽  
J Fischer ◽  
T Maniatis
Keyword(s):  
Fat Body ◽  
Ectopic Expression ◽  
Regulatory Elements ◽  
Transcriptional Enhancer ◽  
Heterologous Promoter ◽  
Larval Tissue ◽  
Drosophila Mulleri ◽  
Sequence Elements ◽  
Enhancer Function ◽  
Upstream Element

Abstract The Adh-2 gene of Drosophila mulleri is expressed in the larval fat body and the adult fat body and hindgut, and a 1500-bp element located 2-3 kb upstream of the Adh-2 promoter is necessary for maximal levels of transcription. Previous work demonstrated that deletion of sequences between this upstream element and the Adh-2 promoter results in Adh-2 gene expression in a novel larval tissue, the middle midgut. In this study we show that the upstream element possesses all of the characteristics of a transcriptional enhancer: its activity is independent of orientation, it acts on a heterologous promoter, and it functions at various positions both 5' and 3' to the Adh-2 gene. Full enhancer function can be localized to a 750-bp element, although other regions possess some redundant activity. The ectopic expression pattern is dependent on the proximity of at least two sequence elements. Thus, tissue-specific transcription can involve complex proximity-dependent interactions among combinations of regulatory elements.

scholarly journals Bayesian Linear Mixed Models for Motif Activity Analysis

2019 ◽  
Author(s):  
Simone Lederer ◽  
Tom Heskes ◽  
Simon J. van Heeringen ◽  
Cornelis A. Albers
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Ridge Regression ◽  
Mixed Model ◽  
Target Genes ◽  
Linear Mixed Model ◽  
Covariance Structure ◽  
Regulatory Elements ◽  
Mathematical Explanation ◽  
Experimental Conditions

AbstractMotivationCellular identity and behavior is controlled by complex gene regulatory networks. Transcription factors (TFs) bind to specific DNA sequences to regulate the transcription of their target genes. On the basis of these TF motifs in cis-regulatory elements we can model the influence of TFs on gene expression. In such models of TF motif activity the data is usually modeled assuming a linear relationship between the motif activity and the gene expression level. A commonly used method to model motif influence is based on Ridge Regression. One important assumption of linear regression is the independence between samples. However, if samples are generated from the same cell line, tissue, or other biological source, this assumption may be invalid. This same assumption of independence is also applied to different, yet similar, experimental conditions, which may also be inappropriate. In theory, the independence assumption between samples could lead to loss in signal detection. Here we investigate whether a Bayesian model that allows for correlations results in more accurate inference of motif activities.ResultsWe extend the Ridge Regression to a Bayesian Linear Mixed Model, which allows us to model dependence between different samples. In a simulation study, we in-vestigate the differences between the two model assumptions. We show that our Bayesian Linear Mixed Model implementation outperforms Ridge Regression in a simulation scenario where the noise, the signal that can not be explained by TF motifs, is uncorrelated. However, we demonstrate that there is no such gain in performance if the noise has a similar covariance structure over samples as the signal that can be explained by motifs. We give a mathematical explanation to why this is the case. Using two representative real data sets we show that at most ∼ 40% of the signal is explained by motifs using the linear model. With these data there is no advantage to using the Bayesian Linear Mixed Model, due to the similarity of the covariance structure.Availability & ImplementationThe project implementation is available at https://github.com/Sim19/SimGEXPwMotifs.

scholarly journals Influence of genetic polymorphism on transcriptional enhancer activity in the malaria vector Anopheles coluzzii

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Luisa Nardini ◽  
Inge Holm ◽  
Adrien Pain ◽  
Emmanuel Bischoff ◽  
Daryl M. Gohl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Malaria Vector ◽  
Functional Activity ◽  
Regulatory Elements ◽  
Transmission Efficiency ◽  
Luciferase Reporter ◽  
Anopheles Coluzzii ◽  
Transcriptional Enhancer ◽  
Enhancer Activity ◽  
Enhancer Sequences

Abstract Enhancers are cis-regulatory elements that control most of the developmental and spatial gene expression in eukaryotes. Genetic variation of enhancer sequences is known to influence phenotypes, but the effect of enhancer variation upon enhancer functional activity and downstream phenotypes has barely been examined in any species. In the African malaria vector, Anopheles coluzzii, we identified candidate enhancers in the proximity of genes relevant for immunity, insecticide resistance, and development. The candidate enhancers were functionally validated using luciferase reporter assays, and their activity was found to be essentially independent of their physical orientation, a typical property of enhancers. All of the enhancers segregated genetically polymorphic alleles, which displayed significantly different levels of functional activity. Deletion mutagenesis and functional testing revealed a fine structure of positive and negative regulatory elements that modulate activity of the enhancer core. Enhancer polymorphisms segregate in wild A. coluzzii populations in West Africa. Thus, enhancer variants that modify target gene expression leading to likely phenotypic consequences are frequent in nature. These results demonstrate the existence of naturally polymorphic A. coluzzii enhancers, which may help explain important differences between individuals or populations for malaria transmission efficiency and vector adaptation to the environment.

scholarly journals A tissue-specific transcriptional enhancer is found in the body of the HLA-DR alpha gene.

1987 ◽  
Vol 166 (3) ◽  
pp. 625-636 ◽  
Author(s):  
Y Wang ◽  
A S Larsen ◽  
B M Peterlin
Keyword(s):  
Dna Sequences ◽  
Regulatory Elements ◽  
Chloramphenicol Acetyltransferase ◽  
The Body ◽  
Transcriptional Enhancer ◽  
Tissue Specific ◽  
Cis Acting ◽  
Hla Dr ◽  
Hypersensitive Sites ◽  
Alpha Gene

We mapped cis-acting regulatory elements in the HLA-DR alpha gene, which encodes the monomorphic subunit of the HLA-DR heterodimer. Genomic fragments of HLA-DR alpha were placed 5' or 3' to the chloramphenicol acetyltransferase reporter gene, the transcription of which was initiated from the Herpes simplex thymidine kinase promoter. In transient expression assays, fragments from the body of the HLA-DR alpha gene were able to increase chloramphenicol acetyltransferase activity in a position-, orientation-, and promoter-independent yet tissue-specific fashion. These HLA-DR alpha cis-acting regulatory elements contain previously identified DNase I-hypersensitive sites and DNA sequences homologous to those found in other eukaryotic transcriptional enhancers.

scholarly journals Distinct gene expression patterns in skeletal and cardiac muscle are dependent on common regulatory sequences in the MLC1/3 locus.

1996 ◽  
Vol 16 (8) ◽  
pp. 4524-4534 ◽  
Author(s):  
M J McGrew ◽  
N Bogdanova ◽  
K Hasegawa ◽  
S H Hughes ◽  
R N Kitsis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Cardiac Muscle ◽  
Consensus Sequence ◽  
Expression Patterns ◽  
Methylation Status ◽  
Regulatory Elements ◽  
Protein Isoforms ◽  
Regulatory Sequences ◽  
Enhancer Element

The myosin light-chain 1/3 locus (MLC1/3) is regulated by two promoters and a downstream enhancer element which produce two protein isoforms in fast skeletal muscle at distinct stages of mouse embryogenesis. We have analyzed the expression of transcripts from the internal MLC3 promoter and determined that it is also expressed in the atria of the heart. Expression from the MLC3 promoter in these striated muscle lineages is differentially regulated during development. In transgenic mice, the MLC3 promoter is responsible for cardiac-specific reporter gene expression while the downstream enhancer augments expression in skeletal muscle. Examination of the methylation status of endogenous and transgenic promoter and enhancer elements indicates that the internal promoter is not regulated in a manner similar to that of the MLC1 promoter or the downstream enhancer. A GATA protein consensus sequence in the proximal MLC3 promoter but not the MLC1 promoter binds with high affinity to GATA-4, a cardiac muscle- and gut-specific transcription factor. Mutation of either the MEF2 or GATA motifs in the MLC3 promoter attenuates its activity in both heart and skeletal muscles, demonstrating that MLC3 expression in these two diverse muscle types is dependent on common regulatory elements.

scholarly journals t(8;21)(q22;q22) fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA-binding sequences to differentially regulate gene expression

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1392-1401 ◽  
Author(s):  
Akiko J. Okumura ◽  
Luke F. Peterson ◽  
Fumihiko Okumura ◽  
Anita Boyapati ◽  
Dong-Er Zhang
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Binding Site ◽  
Dna Sequences ◽  
Fusion Proteins ◽  
Target Genes ◽  
Regulatory Elements ◽  
Chromosome Abnormalities ◽  
Cancer Development ◽  
Dna Binding Site

AbstractChromosome abnormalities are frequently associated with cancer development. The 8;21(q22;q22) chromosomal translocation is one of the most common chromosome abnormalities identified in leukemia. It generates fusion proteins between AML1 and ETO. Since AML1 is a well-defined DNA-binding protein, AML1-ETO fusion proteins have been recognized as DNA-binding proteins interacting with the same consensus DNA-binding site as AML1. The alteration of AML1 target gene expression due to the presence of AML1-ETO is related to the development of leukemia. Here, using a 25-bp random double-stranded oligonucleotide library and a polymerase chain reaction (PCR)-based DNA-binding site screen, we show that compared with native AML1, AML1-ETO fusion proteins preferentially bind to DNA sequences with duplicated AML1 consensus sites. This finding is further confirmed by both in vitro and in vivo DNA-protein interaction assays. These results suggest that AML1-ETO fusion proteins have a selective preference for certain AML1 target genes that contain multimerized AML1 consensus sites in their regulatory elements. Such selected regulation provides an important molecular mechanism for the dysregulation of gene expression during cancer development.

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