Host Gene Regulation by Transposable Elements: The New, the Old and the Ugly

The human genome has been under selective pressure to evolve in response to emerging pathogens and other environmental challenges. Genome evolution includes the acquisition of new genes or new isoforms of genes and changes to gene expression patterns. One source of genome innovation is from transposable elements (TEs), which carry their own promoters, enhancers and open reading frames and can act as ‘controlling elements’ for our own genes. TEs include LINE-1 elements, which can retrotranspose intracellularly and endogenous retroviruses (ERVs) that represent remnants of past retroviral germline infections. Although once pathogens, ERVs also represent an enticing source of incoming genetic material that the host can then repurpose. ERVs and other TEs have coevolved with host genes for millions of years, which has allowed them to become embedded within essential gene expression programmes. Intriguingly, these host genes are often subject to the same epigenetic control mechanisms that evolved to combat the TEs that now regulate them. Here, we illustrate the breadth of host gene regulation through TEs by focusing on examples of young (The New), ancient (The Old), and disease-causing (The Ugly) TE integrants.

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Gut Microbiota Has a Widespread and Modifiable Effect on Host Gene Regulation

mSystems ◽

10.1128/msystems.00323-18 ◽

2019 ◽

Vol 4 (5) ◽

Cited By ~ 18

Author(s):

Allison L. Richards ◽

Amanda L. Muehlbauer ◽

Adnan Alazizi ◽

Michael B. Burns ◽

Anthony Findley ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Gut Microbiota ◽

Complex Traits ◽

Chromatin Accessibility ◽

Host Gene ◽

Host Cells ◽

Host Gene Expression ◽

Host Genes

ABSTRACT Variation in gut microbiome is associated with wellness and disease in humans, and yet the molecular mechanisms by which this variation affects the host are not well understood. A likely mechanism is that of changing gene regulation in interfacing host epithelial cells. Here, we treated colonic epithelial cells with live microbiota from five healthy individuals and quantified induced changes in transcriptional regulation and chromatin accessibility in host cells. We identified over 5,000 host genes that change expression, including 588 distinct associations between specific taxa and host genes. The taxa with the strongest influence on gene expression alter the response of genes associated with complex traits. Using ATAC-seq, we showed that a subset of these changes in gene expression are associated with changes in host chromatin accessibility and transcription factor binding induced by exposure to gut microbiota. We then created a manipulated microbial community with titrated doses of Collinsella, demonstrating that manipulation of the composition of the microbiome under both natural and controlled conditions leads to distinct and predictable gene expression profiles in host cells. Taken together, our results suggest that specific microbes play an important role in regulating expression of individual host genes involved in human complex traits. The ability to fine-tune the expression of host genes by manipulating the microbiome suggests future therapeutic routes. IMPORTANCE The composition of the gut microbiome has been associated with various aspects of human health, but the mechanism of this interaction is still unclear. We utilized a cellular system to characterize the effect of the microbiome on human gene expression. We showed that some of these changes in expression may be mediated by changes in chromatin accessibility. Furthermore, we validate the role of a specific microbe and show that changes in its abundance can modify the host gene expression response. These results show an important role of gut microbiota in regulating host gene expression and suggest that manipulation of microbiome composition could be useful in future therapies.

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Microbial control of host gene regulation and the evolution of host–microbiome interactions in primates

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0598 ◽

2020 ◽

Vol 375 (1808) ◽

pp. 20190598 ◽

Cited By ~ 1

Author(s):

Laura Grieneisen ◽

Amanda L. Muehlbauer ◽

Ran Blekhman

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Host Species ◽

Evolutionary Dynamics ◽

Microbial Control ◽

Host Gene ◽

Primate Species ◽

Microbiome Composition ◽

Wide Range ◽

Species Specific

Recent comparative studies have found evidence consistent with the action of natural selection on gene regulation across primate species. Other recent work has shown that the microbiome can regulate host gene expression in a wide range of relevant tissues, leading to downstream effects on immunity, metabolism and other biological systems in the host. In primates, even closely related host species can have large differences in microbiome composition. One potential consequence of these differences is that host species-specific microbial traits could lead to differences in gene expression that influence primate physiology and adaptation to local environments. Here, we will discuss and integrate recent findings from primate comparative genomics and microbiome research, and explore the notion that the microbiome can influence host evolutionary dynamics by affecting gene regulation across primate host species. This article is part of the theme issue ‘The role of the microbiome in host evolution’.

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Mobility and Invasion Related Gene Expression Patterns in Equine Sarcoid

Animals ◽

10.3390/ani10050880 ◽

2020 ◽

Vol 10 (5) ◽

pp. 880

Author(s):

Przemysław Podstawski ◽

Wojciech Witarski ◽

Tomasz Szmatoła ◽

Monika Bugno-Poniewierska ◽

Katarzyna Ropka-Molik

Keyword(s):

Gene Expression ◽

Cell Cycle Control ◽

Expression Patterns ◽

Culture Conditions ◽

New Genes ◽

Equine Sarcoid ◽

Common Skin ◽

Skin Biopsies ◽

Pcr Method ◽

Molecular Aspects

Sarcoids are the most common skin neoplasm in the Equidae family. Sarcoids are benign, but may cause severe damage in affected animals. Due to the high risk of post-treatment recurrence and the lack of an effective method of treatment, it is reasonable to perform studies on the molecular aspects of this neoplasm. Therefore, the present studies analyzed five genes (cell cycle control binding protein alpha, coronin 1b, metalloproteinase 2, tissue inhibitor of metalloproteinases 3 and vimentin) related to cell mobility and invasion traits. Primary healthy fibroblasts and sarcoid cells were obtained from skin biopsies. Cell lines were cultured in two different medium types with different concentrations of foetal bovine serum (10% and 0.5% FBS) to study its influence on the analyzed genes. Gene expression was measured using the real-time PCR method. The results showed significant differences in two genes (coronin and vimentin) depending on culture conditions. In conclusion, the results enabled finding two new genes, related to cell motility and invasion traits, in which gene expression is deregulated. Results of the study may put new knowledge into the complexity of the genetic background of this disease and show the importance of further analysis on this subject.

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Impact of Transposable Elements on Methylation and Gene Expression across Natural Accessions of Brachypodium distachyon

Genome Biology and Evolution ◽

10.1093/gbe/evaa180 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1994-2001 ◽

Cited By ~ 1

Author(s):

Michele Wyler ◽

Christoph Stritt ◽

Jean-Claude Walser ◽

Célia Baroux ◽

Anne C Roulin

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Transposable Elements ◽

Brachypodium Distachyon ◽

Large Fraction ◽

Expression Patterns ◽

Specific Gene ◽

Differential Gene ◽

The Relationship ◽

Silent State

Abstract Transposable elements (TEs) constitute a large fraction of plant genomes and are mostly present in a transcriptionally silent state through repressive epigenetic modifications, such as DNA methylation. TE silencing is believed to influence the regulation of adjacent genes, possibly as DNA methylation spreads away from the TE. Whether this is a general principle or a context-dependent phenomenon is still under debate, pressing for studying the relationship between TEs, DNA methylation, and nearby gene expression in additional plant species. Here, we used the grass Brachypodium distachyon as a model and produced DNA methylation and transcriptome profiles for 11 natural accessions. In contrast to what is observed in Arabidopsis thaliana, we found that TEs have a limited impact on methylation spreading and that only few TE families are associated with a low expression of their adjacent genes. Interestingly, we found that a subset of TE insertion polymorphisms is associated with differential gene expression across accessions. Thus, although not having a global impact on gene expression, distinct TE insertions may contribute to specific gene expression patterns in B. distachyon.

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Impact of transposable elements on methylation and gene expression across natural accessions of Brachypodium distachyon

10.1101/2020.06.16.154047 ◽

2020 ◽

Cited By ~ 1

Author(s):

Michele Wyler ◽

Christoph Stritt ◽

Jean-Claude Walser ◽

Célia Baroux ◽

Anne C. Roulin

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Transposable Elements ◽

Plant Species ◽

Brachypodium Distachyon ◽

Expression Patterns ◽

Small Subset ◽

Molecular Evidence ◽

Specific Gene ◽

Plant Genomes

AbstractTransposable elements (TEs) constitute a large fraction of plant genomes and are mostly present in a transcriptionally silent state through repressive epigenetic modifications such as DNA methylation. TE silencing is believed to influence the regulation of adjacent genes, possibly as DNA methylation spreads away from the TE. Whether this is a general principle or a context-dependent phenomenon is still under debate, pressing for studying the relationship between TEs, DNA methylation and nearby gene expression in additional plant species. Here we used the grass Brachypodium distachyon as a model and produced DNA methylation and transcriptome profiles for eleven natural accessions. In contrast to what is observed in Arabidopsis thaliana, we found that TEs have a limited impact on methylation spreading and that only few TE families are associated to a low expression of their adjacent genes. Interestingly, we found that a subset of TE insertion polymorphisms is associated with differential gene expression across accessions. Thus, although not having a global impact on gene expression, distinct TE insertions may contribute to specific gene expression patterns in B. distachyon.Significance statementTransposable elements (TEs) are a major component of plant genomes and a source of genetic and epigenetic innovations underlying adaptation to changing environmental conditions. Yet molecular evidence linking TE silencing and nearby gene expression are lacking for many plant species. We show that in the model grass Brachypodium DNA methylation spreads over very short distances around TEs, with an influence on gene expression for a small subset of TE families.

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Identification of Novel Potential Genes Involved in Cancer by Integrated Comparative Analyses

International Journal of Molecular Sciences ◽

10.3390/ijms21249560 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9560

Author(s):

Francesco Monticolo ◽

Emanuela Palomba ◽

Maria Luisa Chiusano

Keyword(s):

Gene Expression ◽

Cell Death ◽

Programmed Cell Death ◽

Homo Sapiens ◽

Expression Patterns ◽

Comparative Approach ◽

Expression Data ◽

New Genes ◽

Conserved Genes ◽

Multiple Species

The main hallmarks of cancer diseases are the evasion of programmed cell death, uncontrolled cell division, and the ability to invade adjacent tissues. The explosion of omics technologies offers challenging opportunities to identify molecular agents and processes that may play relevant roles in cancer. They can support comparative investigations, in one or multiple experiments, exploiting evidence from one or multiple species. Here, we analyzed gene expression data from induction of programmed cell death and stress response in Homo sapiens and compared the results with Saccharomyces cerevisiae gene expression during the response to cell death. The aim was to identify conserved candidate genes associated with Homo sapiens cell death, favored by crosslinks based on orthology relationships between the two species. We identified differentially-expressed genes, pathways that are significantly dysregulated across treatments, and characterized genes among those involved in induced cell death. We investigated on co-expression patterns and identified novel genes that were not expected to be associated with death pathways, that have a conserved pattern of expression between the two species. Finally, we analyzed the resulting list by HumanNet and identified new genes predicted to be involved in cancer. The data integration and the comparative approach between distantly-related reference species that were here exploited pave the way to novel discoveries in cancer therapy and also contribute to detect conserved genes potentially involved in programmed cell death.

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Aberrant Co-Expression of Micrornas and Host Genes in Leukemia: Evidence for a Common Transcript from Meta-Analysis and Microarray Data.

Blood ◽

10.1182/blood.v108.11.2232.2232 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2232-2232

Author(s):

Serban San-Marina ◽

Fernando Suarez Saiz ◽

Haytham Khoury ◽

Mark D. Minden

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Gene Expression Data ◽

Microarray Data ◽

Meta Analysis ◽

Host Gene ◽

Expression Data ◽

Host Gene Expression ◽

Intronic Mirnas ◽

Host Genes

Abstract In leukemia, the integrity of the transcriptome is altered by chromosomal translocations, deletions, duplications, as well as by epigenetic changes in chromatin structure. By targeting mRNAs for translational repression or RNase-dependent hydrolysis (AU-rich miRNAs or shRNA-like effects), the micro RNA (miRNA) component of the transcriptome is estimated to regulate expression of up to 30% of all proteins. Yet the causes and role of deregulated miRNA expression in malignancy are largely unknown, in part because promoter events are not characterized. Since more than one-third of all known mammalian miRNA genes are encoded in the introns of protein-coding genes they may be regulated by the same promoter events that regulate host-gene mRNA expression. To provide experimental validation for coordinated expression of miRNAs and their host genes we compared Affymetrix U133A gene expression data for the promyelocytic NB4 and acute myelogenous leukemia AML2 cell lines with the expression of miRNA precursors. We found similar patterns of host gene expression in the two cell lines and a good correlation with the expression of miRNA precursors in NB4 cells (r=0.464, N=30 miRNAs, p<0.016). To further demonstrate that host gene mRNAs and miRNAs are expressed from common transcripts, we activated promoter events by enforcing the expression of Lyl1 a basic helix-loop-helix transcription factor that is often over-expressed in AML. This resulted in a greater than 2-fold increase in hsa-mir-126-1, 032-2, 107-1, 026a, -023b, -103-2, and 009-3-1 intronic miRNA precursors and a corresponding increase in host gene expression. Meta-analysis of microarray data across many experiments and platforms (available through Oncomine.org) has been used to study the cancer transcriptome. To help determine if intronic miRNAs play a substantial role in malignancy, we correlated host gene expression data with the expression of predicted miRNA targets. Less than 20% of all differentially expressed genes in leukemia and lymphoma were predicted targets, compared to 68% in breast cancer. Since the Gene Ontology term “ion binding” is most commonly associated with miRNA host genes, the data suggest that this cancer module is relatively inactive in leukemia and lymphoma, compared to breast cancer. Gene cluster analysis of a leukemia data set using only miRNA host gene expression was able to classify patients into similar (but not identical) subsets as did an analysis based on over 20,000 transcripts. To further demonstrate that miRNAs and their host genes are expressed from the same transcription unit, we correlated the expression of miRNA targets with that of genes that are either hosts for miRNAs or are situated several kilobases downstream of a miRNA, and thus belong to different transcription units. We applied this analysis to a subset of 81 AML patients that presented a normal karyotype and found significant negative correlations (p<0.01) between the levels of host genes for hsa-mir-15b, -103-1, and -128 and the expression ranks of their predicted gene targets, but no statistically significant correlation between non-host genes and targets for up-stream miRNAs. These data demonstrate co-regulated expression of host genes and intronic miRNAs and the usefulness of intronic miRNAs in cancer profiling.

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Transcriptional profiling of medulloblastoma in children

Journal of Neurosurgery ◽

10.3171/jns.2003.99.3.0534 ◽

2003 ◽

Vol 99 (3) ◽

pp. 534-541 ◽

Cited By ~ 31

Author(s):

Paul C. Park ◽

Michael D. Taylor ◽

Todd G. Mainprize ◽

Laurence E. Becker ◽

Michael Ho ◽

...

Keyword(s):

Gene Expression ◽

Microarray Analysis ◽

Expression Patterns ◽

Immunohistochemical Analysis ◽

High Mobility Group Protein ◽

Content Type ◽

Expression Levels ◽

Histone Deacetylase 2 ◽

New Genes ◽

Fine Print

Object. Although medulloblastoma is the most common malignant brain tumor found in children, little is known about its molecular pathogenesis. The authors have attempted to compare patterns of gene expression in medulloblastoma samples with those in the healthy cerebellum. Methods. The authors used complementary (c)DNA microarray analysis to compare the expression of genes in samples of medulloblastoma and normal cerebellum. The expression levels of a subset of genes were then verified by immunohistochemical analysis. Six genes were identified that were expressed at a much higher level in at least five of six medulloblastomas: ezrin, cyclin D2, high mobility group protein 2, MAPRE1, histone deacetylase 2, and ornithine decarboxylase 1. A number of potentially important genes whose expression was much lower in medulloblastomas than in control cerebellum were also identified: tenascin R, TRK-B, FGF receptor, and death receptor 3. The expression levels of a subset of the identified genes were confirmed by immunohistochemical analysis, which was performed on fetal cerebellum and medulloblastoma samples. Conclusions. The authors demonstrate that cDNA microarray analysis is an effective method of increasing understanding of the molecular biology of medulloblastomas found in children. A comparison between gene expression patterns in medulloblastoma and those observed in healthy cerebellum may provide clues as to the origin of these tumors and may lead to the identification of new genes or pathways to be targeted for future therapies.

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Identification of Genes Involved in the Host Response to Neurovirulent Alphavirus Infection

Journal of Virology ◽

10.1128/jvi.75.21.10431-10445.2001 ◽

2001 ◽

Vol 75 (21) ◽

pp. 10431-10445 ◽

Cited By ~ 67

Author(s):

Christine Johnston ◽

Wenxia Jiang ◽

Tearina Chu ◽

Beth Levine

Keyword(s):

Gene Expression ◽

Amino Acid ◽

Virus Infection ◽

Sindbis Virus ◽

Mitochondrial Protein ◽

Benzodiazepine Receptor ◽

Host Gene ◽

Single Amino Acid ◽

Amino Acid Mutations ◽

Host Genes

ABSTRACT Single-amino-acid mutations in Sindbis virus proteins can convert clinically silent encephalitis into uniformly lethal disease. However, little is known about the host gene response during avirulent and virulent central nervous system (CNS) infections. To identify candidate host genes that modulate alphavirus neurovirulence, we utilized GeneChip Expression analysis to compare CNS gene expression in mice infected with two strains of Sindbis virus that differ by one amino acid in the E2 envelope glycoprotein. Infection with Sindbis virus, dsTE12H (E2-55 HIS), resulted in 100% mortality in 10-day-old mice, whereas no disease was observed in mice infected with dsTE12Q (E2-55 GLN). dsTE12H, compared with dsTE12Q, replicated to higher titers in mouse brain and induced more CNS apoptosis. Infection with the neurovirulent dsTE12H strain was associated with both a greater number of host genes with increased expression and greater changes in levels of host gene expression than was infection with the nonvirulent dsTE12Q strain. In particular, dsTE12H infection resulted in greater increases in the levels of mRNAs encoding chemokines, proteins involved in antigen presentation and protein degradation, complement proteins, interferon-regulated proteins, and mitochondrial proteins. At least some of these increases may be beneficial for the host, as evidenced by the demonstration that enforced expression of the antiapoptotic mitochondrial protein peripheral benzodiazepine receptor (PBR) protects neonatal mice against lethal Sindbis virus infection. Thus, our findings identify specific host genes that may play a role in the host protective or pathologic response to neurovirulent Sindbis virus infection.

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Endogenous siRNAs: regulators of internal affairs

Biochemical Society Transactions ◽

10.1042/bst20140068 ◽

2014 ◽

Vol 42 (4) ◽

pp. 1174-1179 ◽

Cited By ~ 37

Author(s):

Monica J. Piatek ◽

Andreas Werner

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Drosophila Melanogaster ◽

Transposable Elements ◽

Essential Role ◽

Viral Infections ◽

Biological Functions ◽

Small Interfering Rnas ◽

Argonaute Proteins ◽

Genome Protection

Endo-siRNAs (endogenous small-interfering RNAs) have recently emerged as versatile regulators of gene expression. They derive from double-stranded intrinsic transcripts and are processed by Dicer and associate with Argonaute proteins. In Caenorhabditis elegans, endo-siRNAs are known as 22G and 26G RNAs and are involved in genome protection and gene regulation. Drosophila melanogaster endo-siRNAs are produced with the help of specific Dicer and Argonaute isoforms and play an essential role in transposon control and the protection from viral infections. Biological functions of endo-siRNAs in vertebrates include repression of transposable elements and chromatin organization, as well as gene regulation at the transcriptional and post-transcriptional levels.

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