Inheritance of phenotype in mammalian cells: genetic vs. epigenetic mechanisms

1991 ◽  
Vol 260 (6) ◽  
pp. L386-L394 ◽  
Author(s):  
D. C. Gruenert ◽  
A. L. Cozens
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Growth Regulation ◽  
Cultured Cells ◽  
Protein Complexes ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Epigenetic Mechanisms ◽  
Phenotypic Changes ◽  
Pathways Analysis

Inherited phenotypic changes in cultured cells, as observed during differentiation and transformation, reflect alterations in gene expression and have both a genetic and epigenetic basis. The causes of specific changes are often difficult to define especially when observing phenomenological end points. Although such observations are an important step in defining the phenotypic changes that endure for multiple generations, it is necessary to analyze cells at the molecular level to characterize the pathways leading to changes in phenotype. Gene expression can be regulated at multiple levels, i.e., DNA structure, gene transcription, and/or posttranscriptional modifications. Four genetic mechanisms (DNA point mutations, deletion, rearrangement, and amplification) and two epigenetic mechanisms (DNA methylation and the preservation of DNA-protein complexes) can account for the majority of enduring changes observed in cultured cells. Genetic alterations in DNA sequence appear to be largely responsible for altered growth regulation associated with transformation, but there is also evidence to suggest that epigenetic mechanisms play a role in transformation. Differentiation of cultured cells is often associated with lack of growth, and has been ascribed in part to epigenetic mechanisms. However, differentiation and transformation are not mutually exclusive but may be regulated by parallel multistep pathways. Analysis of the causes underlying transformation has been complicated by the use of aneuploid cells, but it is clear that the tools for overcoming the ambiguities associated with phenomenological analysis are available.

scholarly journals Precise genome engineering inDrosophilausing prime editing

2020 ◽  
Vol 118 (1) ◽  
pp. e2021996118
Author(s):  
Justin A. Bosch ◽  
Gabriel Birchak ◽  
Norbert Perrimon
Keyword(s):  
Gene Function ◽  
Mammalian Cells ◽  
Genome Engineering ◽  
Cultured Cells ◽  
Germ Line ◽  
Point Mutations ◽  
Model Organism ◽  
Model Organisms ◽  
Marker Genes ◽  
Germ Line Transmission

Precise genome editing is a valuable tool to study gene function in model organisms. Prime editing, a precise editing system developed in mammalian cells, does not require double-strand breaks or donor DNA and has low off-target effects. Here, we applied prime editing for the model organismDrosophila melanogasterand developed conditions for optimal editing. By expressing prime editing components in cultured cells or somatic cells of transgenic flies, we precisely introduce premature stop codons in three classical visible marker genes,ebony,white, andforked. Furthermore, by restricting editing to germ cells, we demonstrate efficient germ-line transmission of a precise edit inebonyto 36% of progeny. Our results suggest that prime editing is a useful system inDrosophilato study gene function, such as engineering precise point mutations, deletions, or epitope tags.

scholarly journals Epigenetic Regulatory Mechanisms Associated with Infertility

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Sheroy Minocherhomji ◽  
Prochi F. Madon ◽  
Firuza R. Parikh
Keyword(s):  
Gene Expression ◽  
Noncoding Rnas ◽  
Genetic Alterations ◽  
Human Condition ◽  
Regulatory Mechanisms ◽  
Epigenetic Mechanisms ◽  
Altered States ◽  
Epigenetic Alterations ◽  
Regulate Gene Expression ◽  
Regulate Gene

Infertility is a complex human condition and is known to be caused by numerous factors including genetic alterations and abnormalities. Increasing evidence from studies has associated perturbed epigenetic mechanisms with spermatogenesis and infertility. However, there has been no consensus on whether one or a collective of these altered states is responsible for the onset of infertility. Epigenetic alterations involve changes in factors that regulate gene expression without altering the physical sequence of DNA. Understanding these altered epigenetic states at the genomic level along with higher order organisation of chromatin in genes associated with infertility and pericentromeric regions of chromosomes, particularly 9 and Y, could further identify causes of idiopathic infertility. Determining the association between DNA methylation, chromatin state, and noncoding RNAs with the phenotype could further determine what possible mechanisms are involved. This paper reviews certain mechanisms of epigenetic regulation with particular emphasis on their possible role in infertility.

scholarly journals Stat3 co-operates with mutant Ezh2Y641F to regulate gene expression and limit the anti-tumor immune response in melanoma

2021 ◽  
Author(s):  
Sarah Zimmerman ◽  
Samantha J Nixon ◽  
Leela Raj ◽  
Pei Yu Chen ◽  
Sofia Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transcriptional Repression ◽  
Point Mutations ◽  
Disease Recurrence ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Polycomb Repressive Complex 2 ◽  
Genetically Engineered Mouse Models

One of the most frequently genetically altered chromatin modifiers in melanoma is the Enhancer of Zeste Homolog 2 (EZH2), the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which methylates lysine 27 on histone 3 (H3K27me3), a chromatin mark associated with transcriptional repression. Genetic alterations in EZH2 in melanoma include amplifications and activating point mutations at tyrosine 641 (Y641). The oncogenic role of EZH2 in melanoma has previously been determined; however, its downstream oncogenic mechanisms remain underexplored. Here, we found that in genetically engineered mouse models, expression of Ezh2Y641F causes up-regulation of a subset of interferon-regulated genes in melanoma cells, suggesting a potential role of the immune system in the pathogenesis of these mutations. Expression of these interferon genes was not a result of changes in H3K27me3, but through a direct and non-canonical interaction between Ezh2 and Signal Transducer And Activator of Transcription 3 (Stat3). We found that Ezh2 directly binds Stat3, and that in the presence of Ezh2Y641F mutant, Stat3 protein is hypermethylated. Expression of Stat3 was required to maintain an anti-tumor immune response and its depletion resulted in faster melanoma progression and disease recurrence. Molecularly, Stat3 and Ezh2 bind together at many genomic loci, and, in association with the rest of the PRC2 complex, repress gene expression. These results suggest that one of the oncogenic mechanisms of Ezh2-mediated melanomagenesis is through evasion of the anti-tumor immune response, and that the immunomodulatory properties of Stat3 are context dependent.

scholarly journals RING1 Interacts with Multiple Polycomb-Group Proteins and Displays Tumorigenic Activity

1999 ◽  
Vol 19 (1) ◽  
pp. 57-68 ◽  
Author(s):  
David P. E. Satijn ◽  
Arie P. Otte
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Mammalian Cells ◽  
Protein Complexes ◽  
Cellular Transformation ◽  
Polycomb Group ◽  
Expression Levels ◽  
Self Association

ABSTRACT Polycomb-group (PcG) proteins form large multimeric protein complexes that are involved in maintaining the transcriptionally repressive state of genes. Previously, we reported that RING1 interacts with vertebrate Polycomb (Pc) homologs and is associated with or is part of a human PcG complex. However, very little is known about the role of RING1 as a component of the PcG complex. Here we undertake a detailed characterization of RING1 protein-protein interactions. By using directed two-hybrid and in vitro protein-protein analyses, we demonstrate that RING1, besides interacting with the human Pc homolog HPC2, can also interact with itself and with the vertebrate PcG protein BMI1. Distinct domains in the RING1 protein are involved in the self-association and in the interaction with BMI1. Further, we find that the BMI1 protein can also interact with itself. To better understand the role of RING1 in regulating gene expression, we overexpressed the protein in mammalian cells and analyzed differences in gene expression levels. This analysis shows that overexpression of RING1 strongly represses En-2, a mammalian homolog of the well-characterized Drosophila PcG target geneengrailed. Furthermore, RING1 overexpression results in enhanced expression of the proto-oncogenes c-jun and c-fos. The changes in expression levels of these proto-oncogenes are accompanied by cellular transformation, as judged by anchorage-independent growth and the induction of tumors in athymic mice. Our data demonstrate that RING1 interacts with multiple human PcG proteins, indicating an important role for RING1 in the PcG complex. Further, deregulation of RING1 expression leads to oncogenic transformation by deregulation of the expression levels of certain oncogenes.

scholarly journals Predicting interactome network perturbations in human cancer: application to gene fusions in acute lymphoblastic leukemia

2014 ◽  
Vol 25 (24) ◽  
pp. 3973-3985 ◽  
Author(s):  
Leon Juvenal Hajingabo ◽  
Sarah Daakour ◽  
Maud Martin ◽  
Reinhard Grausenburger ◽  
Renate Panzer-Grümayer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Human Cancer ◽  
Lymphoblastic Leukemia ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Gene Fusions ◽  
Novel Approach ◽  
Interactome Network ◽  
Cell Acute Lymphoblastic Leukemia

Genomic variations such as point mutations and gene fusions are directly or indirectly associated with human diseases. They are recognized as diagnostic, prognostic markers and therapeutic targets. However, predicting the functional effect of these genetic alterations beyond affected genes and their products is challenging because diseased phenotypes are likely dependent of complex molecular interaction networks. Using as models three different chromosomal translocations—ETV6-RUNX1 (TEL-AML1), BCR-ABL1, and TCF3-PBX1 (E2A-PBX1)—frequently found in precursor-B-cell acute lymphoblastic leukemia (preB-ALL), we develop an approach to extract perturbed molecular interactions from gene expression changes. We show that the MYC and JunD transcriptional circuits are specifically deregulated after ETV6-RUNX1 and TCF3-PBX1 gene fusions, respectively. We also identified the bulk mRNA NXF1-dependent machinery as a direct target for the TCF3-PBX1 fusion protein. Through a novel approach combining gene expression and interactome data analysis, we provide new insight into TCF3-PBX1 and ETV6-RUNX1 acute lymphoblastic leukemia.

scholarly journals Precise genome engineering in Drosophila using prime editing

2020 ◽  
Author(s):  
Justin A. Bosch ◽  
Gabriel Birchak ◽  
Norbert Perrimon
Keyword(s):  
Gene Function ◽  
Mammalian Cells ◽  
Genome Engineering ◽  
Cultured Cells ◽  
Germ Line ◽  
Point Mutations ◽  
Model Organism ◽  
Model Organisms ◽  
Marker Genes ◽  
Germ Line Transmission

AbstractPrecise genome editing is a valuable tool to study gene function in model organisms. Prime editing, a precise editing system developed in mammalian cells, does not require double strand breaks or donor DNA and has low off-target effects. Here, we applied prime editing for the model organism Drosophila melanogaster and developed conditions for optimal editing. By expressing prime editing components in cultured cells or somatic cells of transgenic flies, we precisely installed premature stop codons in three classical visible marker genes, ebony, white, and forked. Furthermore, by restricting editing to germ cells, we demonstrate efficient germ line transmission of a precise edit in ebony to ~50% of progeny. Our results suggest that prime editing is a useful system in Drosophila to study gene function, such as engineering precise point mutations, deletions, or epitope tags.

DNA methylation and epigenetic inheritance

1990 ◽  
Vol 326 (1235) ◽  
pp. 329-338 ◽  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Sequences ◽  
Mammalian Cells ◽  
Germ Line ◽  
Experimental System ◽  
Epigenetic Inheritance ◽  
Epigenetic Mechanisms ◽  
Control Of Gene Expression ◽  
Developmental Programme

Classical genetics has revealed the mechanisms for the transmission of genes from generation to generation, but the strategy of the genes in unfolding the developmental programme remains obscure. Epigenetics comprises the study of the mechanisms that impart temporal and spatial control on the activities of all those genes required for the development of a complex organism from the zygote to the adult. Epigenetic changes in gene activity can be studied in relation to DNA methylation in cultured mammalian cells and it is also possible to isolate and characterize mutants with altered DNA methylase activity. Although this experimental system is quite far removed from the epigenetic controls acting during development it does provide the means to clarify the rules governing the silencing of genes by specific DNA methylation and their reactivation by demethylation. This in turn will facilitate studies on the control of gene expression in somatic cells of the developing organism or the adult. The general principles of epigenetic mechanisms can be defined. There are extreme contrasts between instability or switches in gene expression, such as those in stem-line cells, and the stable heritability of a specialized pattern of gene activities. In some situations cell lineages are known to be important, whereas in others coordinated changes in groups of cells have been demonstrated. Control of numbers of cell divisions and the size of organisms, or parts of organisms, is also essential. The epigenetic determination of gene expression can be reversed or reprogrammed in the germ line. The extent to which methylation or demethylation of specific DNA sequences can help explain these basic epigenetic mechanisms is briefly reviewed.

Epigenetic Mechanisms in Development and Disease

2013 ◽  
Vol 41 (3) ◽  
pp. 697-699 ◽  
Author(s):  
Adele Murrell ◽  
Paul J. Hurd ◽  
Ian C. Wood
Keyword(s):  
Gene Expression ◽  
Significant Role ◽  
Protein Complexes ◽  
Epigenetic Mechanisms ◽  
Annual Symposium ◽  
Post Translational Modifications ◽  
Regulate Gene Expression ◽  
Methylation Of Dna ◽  
Society Annual ◽  
Regulate Gene

Our advances in technology allow us to sequence DNA to uncover genetic differences not only between individuals, but also between normal and diseased cells within an individual. However, there is still a lot we have yet to understand regarding the epigenetic mechanisms that also contribute to our individuality and to disease. The 80th Biochemical Society Annual Symposium entitled Epigenetic Mechanisms in Development and Disease brought together some leading researchers in the field who discussed their latest insights into epigenetic mechanisms. Methylation of DNA has been the focus of much study from both a developmental perspective and imprinting of genes to its contribution to diseases such as cancer. Recently, the modification of methylcytosine to hydoxymethylcytosine within cells was uncovered, which opened a host of potential new mechanisms, and a flurry of new studies are underway to uncover its significance. Epigenetics is not confined to a study of DNA, and the post-translational modifications on the histone proteins have a significant role to play in regulating gene expression. There are many different modifications and, as shown at the Symposium, new variations used by cells are still being uncovered. We are some way to identifying how these modifications are added and removed and the protein complexes responsible for these changes. A focus on the function of the complexes and the interactions between individual modifications to regulate gene expression is advancing our knowledge, as discussed in the accompanying papers, although there are clearly plenty of opportunities for new breakthroughs to be made.

scholarly journals Contribution of Epigenetic Mechanisms in the Regulation of Environmentally-Induced Polyphenism in Insects

Insects ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 649
Author(s):  
Gautier Richard ◽  
Julie Jaquiéry ◽  
Gaël Le Trionnaire
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Current Knowledge ◽  
Epigenetic Mechanisms ◽  
Developmental Transitions ◽  
Phenotypic Changes ◽  
Genome Expression ◽  
Alternative Phenotypes ◽  
Non Coding Rna ◽  
Developmental Switches

Many insect species display a remarkable ability to produce discrete phenotypes in response to changes in environmental conditions. Such phenotypic plasticity is referred to as polyphenism. Seasonal, dispersal and caste polyphenisms correspond to the most-studied examples that are environmentally-induced in insects. Cues that induce such dramatic phenotypic changes are very diverse, ranging from seasonal cues, habitat quality changes or differential larval nutrition. Once these signals are perceived, they are transduced by the neuroendocrine system towards their target tissues where gene expression reprogramming underlying phenotypic changes occur. Epigenetic mechanisms are key regulators that allow for genome expression plasticity associated with such developmental switches. These mechanisms include DNA methylation, chromatin remodelling and histone post-transcriptional modifications (PTMs) as well as non-coding RNAs and have been studied to various extents in insect polyphenism. Differential patterns of DNA methylation between phenotypes are usually correlated with changes in gene expression and alternative splicing events, especially in the cases of dispersal and caste polyphenism. Combinatorial patterns of histone PTMs provide phenotype-specific epigenomic landscape associated with the expression of specific transcriptional programs, as revealed during caste determination in honeybees and ants. Alternative phenotypes are also usually associated with specific non-coding RNA profiles. This review will provide a summary of the current knowledge of the epigenetic changes associated with polyphenism in insects and highlights the potential for these mechanisms to be key regulators of developmental transitions triggered by environmental cues.

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