Special Issue "Gene Expression and Regulation"

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A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (31 October 2012)

Special Issue Editor

Guest Editor
Dr. Mary O'Connell

Medical Research Council, Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK
Website | E-Mail
Interests: RNA editing; RNA Protein interaction; RNA interference

Special Issue Information

Dear Colleagues,

Gene expression and how it is regulated is a fundamental question in biology and therefore its complexity is not surprising. Initially the major focus of research was on transcription factors as the major modulators of gene expression. Then enhancers and enhancer binding proteins were found to be critical for gene expression. In recent years epigenetic changes such as DNA methylation and histone methylation have added layers of complexity as they also regulate gene expression. Long range DNA looping can also influence gene expression as it brings promoters and enhancers proximal to genes. With the availability of high throughput sequencing profiling of gene expression in different tissues and also in different diseases has become a very active area of research. What has become a major challenge is to draw a coherent picture from a large volume of data, of what are key regulators of gene expression. This special issue will cover original research papers on this very broad topic. The submission of reviews is also welcomed.

Dr. Mary O'Connell
Guest Editor

Keywords

  • transcription factors
  • enhancers
  • enhancer binding proteins
  • DNA methylation
  • histone methylation
  • DNA looping
  • expression profiling
  • miRNA and post-translational gene silencing
  • asymmetrical distribution of genetic factors

Published Papers (13 papers)

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Research

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Open AccessArticle A Versatile Tool for Stable Inhibition of microRNA Activity
Biology 2013, 2(3), 861-871; doi:10.3390/biology2030861
Received: 11 April 2013 / Revised: 13 May 2013 / Accepted: 15 May 2013 / Published: 28 June 2013
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Abstract
MicroRNAs (miRNAs) are a class of small RNAs (18–22 nt) that post transcriptionally regulate gene expression by binding to complementary sequences on target mRNAs, resulting in translational repression or target degradation and gene silencing. As aberrant expression of miRNAs is implicated in important
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MicroRNAs (miRNAs) are a class of small RNAs (18–22 nt) that post transcriptionally regulate gene expression by binding to complementary sequences on target mRNAs, resulting in translational repression or target degradation and gene silencing. As aberrant expression of miRNAs is implicated in important diseases including cancer miRNA-based therapies are under intensive investigation. We optimized strategies to stably or conditionally generate miRNA inhibitors for a continuous block of miRNA activity that allows for probing miRNA function in long-term cell culture experiments, cancer xenografts, 3D tissue models and for in vivo studies with transgenic organisms. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
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Open AccessArticle Targeted Toxin-Based Selectable Drug-Free Enrichment of Mammalian Cells with High Transgene Expression
Biology 2013, 2(1), 341-355; doi:10.3390/biology2010341
Received: 24 December 2012 / Revised: 24 December 2012 / Accepted: 29 January 2013 / Published: 28 February 2013
Cited by 6 | PDF Full-text (906 KB) | HTML Full-text | XML Full-text
Abstract
Almost all transfection protocols for mammalian cells use a drug resistance gene for the selection of transfected cells. However, it always requires the characterization of each isolated clone regarding transgene expression, which is time-consuming and labor-intensive. In the current study, we developed a
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Almost all transfection protocols for mammalian cells use a drug resistance gene for the selection of transfected cells. However, it always requires the characterization of each isolated clone regarding transgene expression, which is time-consuming and labor-intensive. In the current study, we developed a novel method to selectively isolate clones with high transgene expression without drug selection. Porcine embryonic fibroblasts were transfected with pCEIEnd, an expression vector that simultaneously expresses enhanced green fluorescent protein (EGFP) and endo-b-galactosidase C(EndoGalC; an enzyme capable of digesting cell surface a-Gal epitope) upon transfection. After transfection, the surviving cells were briefly treated with IB4SAP (a-Gal epitope-specific BS-I-B4 lectin conjugated with a toxin saporin). The treated cells were then allowed to grow in normal medium, during which only cells strongly expressing EndoGalC and EGFP would survive because of the absence of a-Gal epitopes on their cell surface. Almost all the surviving colonies after IB4SAP treatment were in fact negative for BS-I-B4 staining, and also strongly expressed EGFP. This system would be particularly valuable for researchers who wish to perform large-scale production of therapeutically important recombinant proteins. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
Open AccessArticle Cell-Type Specific Determinants of NRAMP1 Expression in Professional Phagocytes
Biology 2013, 2(1), 233-283; doi:10.3390/biology2010233
Received: 25 December 2012 / Revised: 15 January 2013 / Accepted: 15 January 2013 / Published: 25 January 2013
Cited by 2 | PDF Full-text (1463 KB) | HTML Full-text | XML Full-text
Abstract
The Natural resistance-associated macrophage protein 1 (Nramp1 or Solute carrier 11 member 1, Slc11a1) transports divalent metals across the membrane of late endosomes and lysosomes in professional phagocytes. Nramp1 represents an ancient eukaryotic cell-autonomous defense whereas the gene duplication that yielded Nramp1 and
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The Natural resistance-associated macrophage protein 1 (Nramp1 or Solute carrier 11 member 1, Slc11a1) transports divalent metals across the membrane of late endosomes and lysosomes in professional phagocytes. Nramp1 represents an ancient eukaryotic cell-autonomous defense whereas the gene duplication that yielded Nramp1 and Nramp2 predated the origin of Sarcopterygians (lobe-finned fishes and tetrapods). SLC11A1 genetic polymorphisms associated with human resistance to tuberculosis consist of potential regulatory variants. Herein, current knowledge of the regulation of SLC11A1 gene expression is reviewed and comprehensive analysis of ENCODE data available for hematopoietic cell-types suggests a hypothesis for the regulation of SLC11A1 expression during myeloid development and phagocyte functional polarization. SLC11A1 is part of a 34.6 kb CTCF-insulated locus scattered with predicted regulatory elements: a 3' enhancer, a large 5' enhancer domain and four elements spread around the transcription start site (TSS), including several C/EBP and PU.1 sites. SLC11A1 locus ends appear mobilized by ETS-related factors early during myelopoiesis; activation of both 5' and 3' enhancers in myelo-monocytic cells correlate with transcription factor binding at the TSS. Characterizing the corresponding cis/trans determinants functionally will establish the mechanisms involved and possibly reveal genetic variation that impacts susceptibility to infectious or immune diseases. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
Open AccessArticle A Systematic Survey and Characterization of Enhancers that Regulate Sox3 in Neuro-Sensory Development in Comparison with Sox2 Enhancers
Biology 2012, 1(3), 714-735; doi:10.3390/biology1030714
Received: 17 October 2012 / Revised: 6 November 2012 / Accepted: 9 November 2012 / Published: 22 November 2012
Cited by 3 | PDF Full-text (1513 KB) | HTML Full-text | XML Full-text
Abstract
Development of neural and sensory primordia at the early stages of embryogenesis depends on the activity of two B1 Sox transcription factors, Sox2 and Sox3. The embryonic expression patterns of the Sox2 and Sox3 genes are similar, yet they show gene-unique features. We
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Development of neural and sensory primordia at the early stages of embryogenesis depends on the activity of two B1 Sox transcription factors, Sox2 and Sox3. The embryonic expression patterns of the Sox2 and Sox3 genes are similar, yet they show gene-unique features. We screened for enhancers of the 231-kb genomic region encompassing Sox3 of chicken, and identified 13 new enhancers that showed activity in different domains of the neuro-sensory primordia. Combined with the three Sox3-proximal enhancers determined previously, at least 16 enhancers were involved in Sox3 regulation. Starting from the NP1 enhancer, more enhancers with different specificities are activated in sequence, resulting in complex overlapping patterns of enhancer activities. NP1 was activated in the caudal lateral epiblast adjacent to the posterior growing end of neural plate, and by the combined action of Wnt and Fgf signaling, similar to the Sox2 N1 enhancer involved in neural/mesodermal dichotomous cell lineage segregation. The Sox3 D5 enhancer and Sox2 N3 enhancer were also activated similarly in the diencephalon, optic vesicle and lens placode, suggesting analogies in their regulation. In general, however, the specificities of the enhancers were not identical between Sox3 and Sox2, including the cases of the NP1 and D5 enhancers. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)

Review

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Open AccessReview The Role of Nuclear Bodies in Gene Expression and Disease
Biology 2013, 2(3), 976-1033; doi:10.3390/biology2030976
Received: 15 May 2013 / Revised: 13 June 2013 / Accepted: 20 June 2013 / Published: 9 July 2013
Cited by 8 | PDF Full-text (574 KB) | HTML Full-text | XML Full-text
Abstract
This review summarizes the current understanding of the role of nuclear bodies in regulating gene expression. The compartmentalization of cellular processes, such as ribosome biogenesis, RNA processing, cellular response to stress, transcription, modification and assembly of spliceosomal snRNPs, histone gene synthesis and nuclear
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This review summarizes the current understanding of the role of nuclear bodies in regulating gene expression. The compartmentalization of cellular processes, such as ribosome biogenesis, RNA processing, cellular response to stress, transcription, modification and assembly of spliceosomal snRNPs, histone gene synthesis and nuclear RNA retention, has significant implications for gene regulation. These functional nuclear domains include the nucleolus, nuclear speckle, nuclear stress body, transcription factory, Cajal body, Gemini of Cajal body, histone locus body and paraspeckle. We herein review the roles of nuclear bodies in regulating gene expression and their relation to human health and disease. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
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Open AccessReview Dynamic Interplay of Smooth Muscle α-Actin Gene-Regulatory Proteins Reflects the Biological Complexity of Myofibroblast Differentiation
Biology 2013, 2(2), 555-586; doi:10.3390/biology2020555
Received: 25 January 2013 / Revised: 1 March 2013 / Accepted: 6 March 2013 / Published: 28 March 2013
Cited by 3 | PDF Full-text (635 KB) | HTML Full-text | XML Full-text
Abstract
Myofibroblasts (MFBs) are smooth muscle-like cells that provide contractile force required for tissue repair during wound healing. The leading agonist for MFB differentiation is transforming growth factor β1 (TGFβ1) that induces transcription of genes encoding smooth muscle α-actin (SMαA) and interstitial collagen that
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Myofibroblasts (MFBs) are smooth muscle-like cells that provide contractile force required for tissue repair during wound healing. The leading agonist for MFB differentiation is transforming growth factor β1 (TGFβ1) that induces transcription of genes encoding smooth muscle α-actin (SMαA) and interstitial collagen that are markers for MFB differentiation. TGFβ1 augments activation of Smad transcription factors, pro-survival Akt kinase, and p38 MAP kinase as well as Wingless/int (Wnt) developmental signaling. These actions conspire to activate β-catenin needed for expression of cyclin D, laminin, fibronectin, and metalloproteinases that aid in repairing epithelial cells and their associated basement membranes. Importantly, β-catenin also provides a feed-forward stimulus that amplifies local TGFβ1 autocrine/paracrine signaling causing transition of mesenchymal stromal cells, pericytes, and epithelial cells into contractile MFBs. Complex, mutually interactive mechanisms have evolved that permit several mammalian cell types to activate the SMαA promoter and undergo MFB differentiation. These molecular controls will be reviewed with an emphasis on the dynamic interplay between serum response factor, TGFβ1-activated Smads, Wnt-activated β-catenin, p38/calcium-activated NFAT protein, and the RNA-binding proteins, Purα, Purβ, and YB-1, in governing transcriptional and translational control of the SMαA gene in injury-activated MFBs. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
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Open AccessReview PRDM Proteins: Molecular Mechanisms in Signal Transduction and Transcriptional Regulation
Biology 2013, 2(1), 107-141; doi:10.3390/biology2010107
Received: 5 November 2012 / Revised: 27 December 2012 / Accepted: 5 January 2013 / Published: 14 January 2013
Cited by 5 | PDF Full-text (573 KB) | HTML Full-text | XML Full-text
Abstract
PRDM (PRDI-BF1 and RIZ homology domain containing) protein family members are characterized by the presence of a PR domain and a variable number of Zn-finger repeats. Experimental evidence has shown that the PRDM proteins play an important role in gene expression regulation, modifying
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PRDM (PRDI-BF1 and RIZ homology domain containing) protein family members are characterized by the presence of a PR domain and a variable number of Zn-finger repeats. Experimental evidence has shown that the PRDM proteins play an important role in gene expression regulation, modifying the chromatin structure either directly, through the intrinsic methyltransferase activity, or indirectly through the recruitment of chromatin remodeling complexes. PRDM proteins have a dual action: they mediate the effect induced by different cell signals like steroid hormones and control the expression of growth factors. PRDM proteins therefore have a pivotal role in the transduction of signals that control cell proliferation and differentiation and consequently neoplastic transformation. In this review, we describe pathways in which PRDM proteins are involved and the molecular mechanism of their transcriptional regulation. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
Open AccessReview Understanding the Dynamics of Gene Regulatory Systems; Characterisation and Clinical Relevance of cis-Regulatory Polymorphisms
Biology 2013, 2(1), 64-84; doi:10.3390/biology2010064
Received: 1 November 2012 / Revised: 21 December 2012 / Accepted: 4 January 2013 / Published: 9 January 2013
Cited by 2 | PDF Full-text (938 KB) | HTML Full-text | XML Full-text
Abstract
Modern genetic analysis has shown that most polymorphisms associated with human disease are non-coding. Much of the functional information contained in the non-coding genome consists of cis-regulatory sequences (CRSs) that are required to respond to signal transduction cues that direct cell specific
[...] Read more.
Modern genetic analysis has shown that most polymorphisms associated with human disease are non-coding. Much of the functional information contained in the non-coding genome consists of cis-regulatory sequences (CRSs) that are required to respond to signal transduction cues that direct cell specific gene expression. It has been hypothesised that many diseases may be due to polymorphisms within CRSs that alter their responses to signal transduction cues. However, identification of CRSs, and the effects of allelic variation on their ability to respond to signal transduction cues, is still at an early stage. In the current review we describe the use of comparative genomics and experimental techniques that allow for the identification of CRSs building on recent advances by the ENCODE consortium. In addition we describe techniques that allow for the analysis of the effects of allelic variation and epigenetic modification on CRS responses to signal transduction cues. Using specific examples we show that the interactions driving these elements are highly complex and the effects of disease associated polymorphisms often subtle. It is clear that gaining an understanding of the functions of CRSs, and how they are affected by SNPs and epigenetic modification, is essential to understanding the genetic basis of human disease and stratification whilst providing novel directions for the development of personalised medicine. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
Open AccessReview Gene Expression and Regulation in Adrenocortical Tumorigenesis
Biology 2013, 2(1), 26-39; doi:10.3390/biology2010026
Received: 31 October 2012 / Revised: 1 December 2012 / Accepted: 14 December 2012 / Published: 27 December 2012
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Abstract
Adrenocortical tumors are frequently found in the general population, and may be benign adrenocortical adenomas or malignant adrenocortical carcinomas. Unfortunately the clinical, biochemical and histopathological distinction between benign and malignant adrenocortical tumors may be difficult in the absence of widely invasive or metastatic
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Adrenocortical tumors are frequently found in the general population, and may be benign adrenocortical adenomas or malignant adrenocortical carcinomas. Unfortunately the clinical, biochemical and histopathological distinction between benign and malignant adrenocortical tumors may be difficult in the absence of widely invasive or metastatic disease, and hence attention has turned towards a search for molecular markers. The study of rare genetic diseases that are associated with the development of adrenocortical carcinomas has contributed to our understanding of adrenocortical tumorigenesis. In addition, comprehensive genomic hybridization, methylation profiling, and genome wide mRNA and miRNA profiling have led to improvements in our understanding, as well as demonstrated several genes and pathways that may serve as diagnostic or prognostic markers. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
Open AccessReview Genetic and Epigenetic Regulation of CCR5 Transcription
Biology 2012, 1(3), 869-879; doi:10.3390/biology1030869
Received: 7 October 2012 / Revised: 27 November 2012 / Accepted: 3 December 2012 / Published: 13 December 2012
Cited by 2 | PDF Full-text (1025 KB) | HTML Full-text | XML Full-text
Abstract
The chemokine receptor CCR5 regulates trafficking of immune cells of the lymphoid and the myeloid lineage (such as monocytes, macrophages and immature dendritic cells) and microglia. Because of this, there is an increasing recognition of the important role of CCR5 in the pathology
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The chemokine receptor CCR5 regulates trafficking of immune cells of the lymphoid and the myeloid lineage (such as monocytes, macrophages and immature dendritic cells) and microglia. Because of this, there is an increasing recognition of the important role of CCR5 in the pathology of (neuro-) inflammatory diseases such as atherosclerosis and multiple sclerosis. Expression of CCR5 is under the control of a complexly organized promoter region upstream of the gene. The transcription factor cAMP-responsive element binding protein 1 (CREB-1) transactivates the CCR5 P1 promoter. The cell-specific expression of CCR5 however is realized by using various epigenetic marks providing a multivalent chromatin state particularly in monocytes. Here we discuss the transcriptional regulation of CCR5 with a focus on the epigenetic peculiarities of CCR5 transcription. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
Open AccessReview Recruitment of Transcription Complexes to Enhancers and the Role of Enhancer Transcription
Biology 2012, 1(3), 778-793; doi:10.3390/biology1030778
Received: 1 November 2012 / Revised: 21 November 2012 / Accepted: 21 November 2012 / Published: 5 December 2012
Cited by 2 | PDF Full-text (847 KB) | HTML Full-text | XML Full-text
Abstract
Enhancer elements regulate the tissue- and developmental-stage-specific expression of genes. Recent estimates suggest that there are more than 50,000 enhancers in mammalian cells. At least a subset of enhancers has been shown to recruit RNA polymerase II transcription complexes and to generate enhancer
[...] Read more.
Enhancer elements regulate the tissue- and developmental-stage-specific expression of genes. Recent estimates suggest that there are more than 50,000 enhancers in mammalian cells. At least a subset of enhancers has been shown to recruit RNA polymerase II transcription complexes and to generate enhancer transcripts. Here, we provide an overview of enhancer function and discuss how transcription of enhancers or enhancer-generated transcripts could contribute to the regulation of gene expression during development and differentiation. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
Open AccessReview The Role of DNA Methylation in Common Skeletal Disorders
Biology 2012, 1(3), 698-713; doi:10.3390/biology1030698
Received: 25 September 2012 / Revised: 31 October 2012 / Accepted: 16 November 2012 / Published: 22 November 2012
Cited by 3 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text
Abstract
Bone is a complex connective tissue characterized by a calcified extracellular matrix. This mineralized matrix is constantly being formed and resorbed throughout life, allowing the bone to adapt to daily mechanical loads and maintain skeletal properties and composition. The imbalance between bone formation
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Bone is a complex connective tissue characterized by a calcified extracellular matrix. This mineralized matrix is constantly being formed and resorbed throughout life, allowing the bone to adapt to daily mechanical loads and maintain skeletal properties and composition. The imbalance between bone formation and bone resorption leads to changes in bone mass. This is the case of osteoporosis and osteoarthritis, two common skeletal disorders. While osteoporosis is characterized by a decreased bone mass and, consequently, higher susceptibly to fractures, bone mass tends to be higher in patients with osteoarthritis, especially in the subchondral bone region. It is known that these diseases are influenced by heritable factors. However, the DNA polymorphisms identified so far in GWAS explain less than 10% of the genetic risk, suggesting that other factors, and specifically epigenetic mechanisms, are involved in the pathogenesis of these disorders. This review summarizes current knowledge about the influence of epigenetic marks on bone homeostasis, paying special attention to the role of DNA methylation in the onset and progression of osteoporosis and osteoarthritis. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
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Open AccessReview Changes in Cis-regulatory Elements during Morphological Evolution
Biology 2012, 1(3), 557-574; doi:10.3390/biology1030557
Received: 9 July 2012 / Revised: 30 August 2012 / Accepted: 9 October 2012 / Published: 25 October 2012
Cited by 6 | PDF Full-text (333 KB) | HTML Full-text | XML Full-text
Abstract
How have animals evolved new body designs (morphological evolution)? This requires explanations both for simple morphological changes, such as differences in pigmentation and hair patterns between different Drosophila populations and species, and also for more complex changes, such as differences in the forelimbs
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How have animals evolved new body designs (morphological evolution)? This requires explanations both for simple morphological changes, such as differences in pigmentation and hair patterns between different Drosophila populations and species, and also for more complex changes, such as differences in the forelimbs of mice and bats, and the necks of amphibians and reptiles. The genetic changes and pathways involved in these evolutionary steps require identification. Many, though not all, of these events occur by changes in cis-regulatory (enhancer) elements within developmental genes. Enhancers are modular, each affecting expression in only one or a few tissues. Therefore it is possible to add, remove or alter an enhancer without producing changes in multiple tissues, and thereby avoid widespread (pleiotropic) deleterious effects. Ideally, for a given step in morphological evolution it is necessary to identify (i) the change in phenotype, (ii) the changes in gene expression, (iii) the DNA region, enhancer or otherwise, affected, (iv) the mutation involved, (v) the nature of the transcription or other factors that bind to this site. In practice these data are incomplete for most of the published studies upon morphological evolution. Here, the investigations are categorized according to how far these analyses have proceeded. Full article
(This article belongs to the Special Issue Gene Expression and Regulation)
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