Hiwi mediated tumorigenesis is associated with DNA hypermethylation

Expression of Piwi proteins is confined to early development and stem cells during which they suppress transposon migration via DNA methylation to ensure genomic stability. Piwi's genomic protective function conflicts with reports that its human ortholog, Hiwi, is expressed in numerous cancers and prognosticates shorter survival. However, the role of Hiwi in tumorigenesis has not been examined. Here we demonstrate that (1) over-expressing Hiwi in sarcoma precursors inhibits their differentiation in vitro and generates sarcomas in vivo; (2) transgenic mice expressing Hiwi (mesodermally restricted) develop sarcomas; and (3) inducible down-regulation of Hiwi in human sarcomas inhibits growth and re-establishes differentiation. Our data indicates that Hiwi is directly tumorigenic and Hiwi-expressing cancers may be addicted to Hiwi expression. We further show that Hiwi associated DNA methylation and cyclin-dependent kinase inhibitor (CDKI) silencing is reversible along with Hiwi-induced tumorigenesis, via DNA-methyltransferase inhibitors. Our studies reveal for the first time not only a novel oncogenic role for Hiwi as a driver of tumorigenesis, but also suggest that the use of epigenetic agents may be clinically beneficial for treatment of tumors that express Hiwi. Additionally, our data showing that Hiwi-associated DNA hyper-methylation with subsequent genetic and epigenetic changes favoring a tumorigenic state reconciles the conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis.     

Human morbid genetics revisited: relevance of epigenetics

Identification of genes predisposing their carrier to complex diseases is a much more complicated task than finding genes involved in simple mendelian diseases. The slow progress in the genetic research of complex diseases could be due to limitations in the basic research strategy, which is almost exclusively orientated to the detection of disease-related DNA mutations or polymorphisms. I argue in this article that epigenetic misregulation of genes is more consistent with the features of complex diseases than is DNA sequence variation, and therefore that epigenetic factors could be important in understanding the origins of complex diseases.     

Chemical genetics approaches for selective intervention in epigenetics

In conventional chemical genetics, cell-active small-molecules directly block protein activity, altering phenotype. However these molecules may not be sufficiently selective or effective at modulating complex epigenetic pathways. By mutating the target protein, and creating a mutant-selective inhibitor, the bump-and-hole approach can provide single-target selectivity. PROTAC molecules direct their target to proteosomal degradation by recruiting an E3 ubiquitin ligase, resulting in more efficacious target downregulation.

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Dissecting DNA hypermethylation in cancer

There is compelling evidence to support the importance of DNA methylation alterations in cancer development. Both losses and gains of DNA methylation are observed, thought to contribute pathophysiologically by inactivating tumor suppressor genes, inducing chromosomal instability and ectopically activating gene expression. Lesser known are the causes of aberrant DNA methylation. Recent studies have pointed out that intrinsic gene susceptibility to DNA methylation, environmental factors and gene function all have an intertwined participation in this process. Overall, these data support a deterministic rather than a stochastic mechanism for de novo DNA methylation in cancer. In this review article, we discuss the technologies available to study DNA methylation and the endogenous and exogenous factors that influence the onset of de novo methylation in cancer.     

Molecular genetics of cancer and tumorigenesis: Drosophila models

Why do some cells not respond to normal control of cell division and become tumorous? Which signals trigger some tumor cells to migrate and colonize other tissues? What genetic factors are responsible for tumorigenesis and cancer development? What environmental factors play a role in cancer formation and progression? In how many ways can our bodies prevent and restrict the growth of cancerous cells?How can we identify and deliver effective drugs to fight cancer? In the fight against cancer,which kills more people than any other disease,these and other questions have long interested researchers from a diverse range of fields.To answer these questions and to fight cancer more effectively,we must increase our understanding of basic cancer biology.Model organisms,including the fruit fly Drosophila melanogaster,have played instrumental roles in our understanding of this devastating disease and the search for effective cures.Drosophila and its highly effective,easy-touse,and ever-expanding genetic tools have contributed toand enriched our knowledge of cancer and tumor formation tremendously.     

Molecular genetics of cancer and tumorigenesis: Drosophila models

Why do some cells not respond to normal control of cell division and become tumorous? Which signals trigger some tumor cells to migrate and colonize other tissues? What genetic factors are responsible for tumorigenesis and cancer development? What environmental factors play a role in cancer formation and progression? In how many ways can our bodies prevent and restrict the growth of cancerous cells?How can we identify and deliver effective drugs to fight cancer? In the fight against cancer,which kills more people than any other disease,these and other questions have long interested researchers from a diverse range of fields.To answer these questions and to fight cancer more effectively,we must increase our understanding of basic cancer biology.Model organisms,including the fruit fly Drosophila melanogaster,have played instrumental roles in our understanding of this devastating disease and the search for effective cures.Drosophila and its highly effective,easy-touse,and ever-expanding genetic tools have contributed toand enriched our knowledge of cancer and tumor formation tremendously.     

Hsp90 at the crossroads of genetics and epigenetics

Hsp90 is a specialized molecular chaperone that is capable of buffering the expression of abnormal phenotypes.Inhi-bition of Hsp90 activity results in the expression of these phenotypes that are otherwise masked.Selection of offspringfrom the crossing of affected progenies results in inheritance and enrichment of these phenotypes,which can becomeindependent of their original stimuli.The current combined evidence favours a model involving the interplay betweengenetics and epigenetics.The recent proteomics efforts to characterize the Hsp90 interaction networks provide further cluesinto the molecular mechanisms behind this complex phenomenon.This review summarizes the most recent experimentalobservations and briefly discusses the genetic and epigenetic views used in explaining the different observations.     

Aging and epigenetics: longitudinal changes in gene-specific DNA methylation

DNA methylation has been associated with age-related disease. Intra-individual changes in gene-specific DNA methylation over time in a community-based cohort has not been well described. We estimated the change in DNA methylation due to aging for nine genes in an elderly, community-dwelling cohort of men. Seven hundred and eighty four men from the Veterans Administration Normative Aging Study who were living in metropolitan Boston from 1999-2009 donated a blood sample for DNA methylation analysis at clinical examinations repeated at approximately 3-5 year intervals. We used mixed effects regression models. Aging was significantly associated with decreased methylation of GCR, iNOS and TLR2 and with increased methylation of IFNγ, F3, CRAT and OGG. Obstructive pulmonary disease at baseline modified the effect of aging on methylation of IFNγ (interaction p = 0.04). For participants who had obstructive pulmonary disease at their baseline visit, the rate of change of methylation of IFNγ was -0.05% 5-methyl-cytosine (5-mC) per year (95% CI: -0.22, 0.13), but was 0.14% 5-mC per year (95% CI: 0.05, 0.24) for those without this condition. Models with random slopes indicated significant heterogeneity in the effect of aging on methylation of GCR, iNOS and OGG. These findings suggest that DNA methylation may reflect differential biological aging.     

A new stage in the development of genetics and term epigenetics

Genetics requires verification of the notion of gene. In this article, DNA and DNA parts are proposed to be named progenes, while the term gene refers to the informational products produced on DNA. These are RNA genes, protein genes, and DNA genes (transposable elements). The focus of genetics is switched today from characters of intraspecies difference to characters of intraspecies similarity. Regulatory genes controlling ontogeny (ontogenes) become the main object of research. These genes can be isolated by methods of both reverse and direct genetics. The properties of ontogene mutations, isolated by methods of direct genetics, are described. The problematic of epigenetics is related to the expression of ontogenes. The term epigenetics is not correct because of its ambiguity.     

DNA replication origins: from sequence specificity to epigenetics

Site-specific initiation of DNA replication is a conserved function in all organisms. In Escherichia coli and Saccharomyces cerevisiae, DNA replication origins are sequence specific, but in multicellular organisms, origins are not so clearly defined. In this article, I present a model of origin specification by epigenetic mechanisms that allows the establishment of stable chromatin domains, which are characterized by autonomous replication. According to this model, origins of DNA replication help to establish domains of gene expression for the generation of cell diversity.     

Advances in the genetics and epigenetics of gene regulation and human disease

A report on the Human Genome Organisation (HUGO) 11th Human Genome Meeting, Helsinki, Finland, 31 May-3 June 2006.     

Cancer gene silencing without DNA hypermethylation

Both DNA hypermethylation and Polycomb-mediated histone methylation induce gene silencing in cancer, but largely in two separate paths. Hence, different pharmacologic approaches are required to reactivate genes silenced by distinct epigenetic mechanisms.