Altruistic functions for selfish DNA

Roslin Institute, University of Edinburgh, Roslin, Scotland, UK.
Cell cycle (Georgetown, Tex.) (Impact Factor: 5.01). 10/2009; 8(18):2895-900. DOI: 10.4161/cc.8.18.9536
Source: PubMed

ABSTRACT Mammalian genomes are comprised of 30-50% transposed elements (TEs). The vast majority of these TEs are truncated and mutated fragments of retrotransposons that are no longer capable of transposition. Although initially regarded as important factors in the evolution of gene regulatory networks, TEs are now commonly perceived as neutrally evolving and non-functional genomic elements. In a major development, recent works have strongly contradicted this "selfish DNA" or "junk DNA" dogma by demonstrating that TEs use a host of novel promoters to generate RNA on a massive scale across most eukaryotic cells. This transcription frequently functions to control the expression of protein-coding genes via alternative promoters, cis regulatory non protein-coding RNAs and the formation of double stranded short RNAs. If considered in sum, these findings challenge the designation of TEs as selfish and neutrally evolving genomic elements. Here, we will expand upon these themes and discuss challenges in establishing novel TE functions in vivo.


Available from: Piero Carninci, Dec 14, 2013
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    ABSTRACT: Stress plays a substantial role in shaping behavior and brain function, often with lasting effects. How these lasting effects occur in the context of a fixed postmitotic neuronal genome has been an enduring question for the field. Synaptic plasticity and neurogenesis have provided some of the answers to this question, and more recently epigenetic mechanisms have come to the fore. The explo-ration of epigenetic mechanisms recently led us to discover that a single acute stress can regulate the expression of retrotransposons in the rat hippocampus via an epigenetic mechanism. We propose that this response may represent a genomic stress response aimed at maintaining genomic and transcriptional stability in vulnerable brain regions such as the hippocampus. This finding and those of other researchers have made clear that retrotransposons and the genomic plasticity they permit play a significant role in brain func-tion during stress and disease. These observations also raise the possibility that the transposome might have adaptive functions at the level of both evolution and the individual organism. hippocampus | retrotransposon | histone marks | brain | genomic stress response T he brain is the central organ of stress and adaptation to stressors because it not only perceives what is threatening or potentially threatening and initiates behavioral and physiological responses to those challenges but also is a target of the stressful experiences and the hormones and other mediators of the stress response (1–4). The neural and hormonal mediators of the stress response affect most of the body's organ systems, and prolonged or severe stressors can have prolonged physiologic and behav-ioral sequelae that can extend throughout the lifespan and be-yond, to leave its imprint on our offspring (2, 5, 6). Short-term activation of stress mediators can be beneficial to cope with challenges, but long-term activation is accompanied by cumula-tive, potentially detrimental effects referred to, with increasing severity, as "allostatic load and overload" (3, 7, 8) Thus, although the brain is the conductor of this neuroendocrine orchestra, it is also shaped in many ways by its music, with both adaptive and pathogenic results (1, 2, 9). Stress has a well-established influence on brain structure, function, and behavior; however "stress" is not a unitary phe-nomenon, nor are its effects upon individuals entirely predictable. The effects of stress upon an individual are dictated by a number of factors: stress duration, severity, controllability, age, and sex have clearly delineated roles in determining the impact of a par-ticular stressor on an individual (10, 11). An individual's stress history also seems to play an important role in the capacity to resist future stress exposures. Surprisingly, at least from the clas-sical Darwinian perspective, the stress history of parents is a sig-nificant factor in the resilience of their offspring (12). The desire to understand how environmental stress transduces its effects into lasting changes on physiology and behavior, which can vary even among genetically identical individuals, has led scientists to hy-pothesize that epigenetic factors might provide an explanatory mechanism (1, 13, 14). The introduction of next-generation se-quencing technologies to the exploration of epigenetics and stress neurobiology has led to greater attention to the possibility that the largely unexplored genomic space represented by retrotrans-posons might also have functional significance for brain function and stress susceptibility (15–17).
    Proceedings of the National Academy of Sciences 11/2014; DOI:10.1073/pnas.1411260111 · 9.81 Impact Factor
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    ABSTRACT: RNA interference (RNAi) has changed the traditional model of gene regulation by revealing the existence of small regulatory RNA fragments, known as small RNAs (sRNAs), which influence gene expression at the transcriptional and post transcriptional level. The study of sRNAs is currently carried out as a joint effort in molecular biology, high throughput sequencing, bioinformatics analysis and biochemical studies. The book covers these aspects in its three parts: Basics (chapters 1 - 8), Methods (chapters 9 - 15) and Applications (chapters 16 - 21) in an attempt to present a snapshot of a dynamic and prolific field. The first part commences with an overview of the known classes of sRNAs in “Renaissance of the regulatory RNAs”. The junk DNA is reconsidered and further classified into several types of non-coding regulatory RNAs. The brief description of microRNAs, siRNA, piRNA, snoRNA forming the first chapter is smoothly continued in the second chapter “Diversity, overlap and relationships in the small RNA landscape”. Here further details on the biogenesis and mode of actions of sRNAs are presented next to an analysis of the evolutionary relationship between transposable elements and sRNAs. The third chapter explores yet another class of sRNAs, the small nucleolar RNAs (snoRNAs) and highlights high throughput sequencing and RNA protection experiments as methods to facilitate the understanding of their mode of action. The forth chapter focuses on sRNAs in prokaryotes and systematically presents the few known sRNAs in bacteria. Their biogenesis, mode of actions and evolutionary analysis are extended with their integration in regulatory circuits. sRNAs regulating gene expressions through complementary base pairing and sRNAs that bind small proteins are described in detail. Chapters 5, 7, 8 return to eukaryotes and present particular types of sRNA in animals (chapter 5), in neural differentiation and plasticity (chapter 7) and in cancer (chapter 8). In chapter 6 an in-depth description of long non-coding RNAs is presented together with comments on their natural selection. The second part of the book, “Methods”, focusses on the computational methods developed for the analysis of high throughput data sets. The first two chapters introduce two widely used high throughput methods, microarrays and deep sequencing, the first being described in the context of LNA/DNA microarrays and ribonucleoprotein libraries (RNP) and the latter in the context of protocols and tools for improving the quality of second generation sequencing. The preparation of immunoprecipitation libraries and technical aspects including capturing sRNA populations with different 5’ and 3’ ends, reduction of adapter dimers and cross mapping of miRNA variants are discussed in detail. Chapters 11 and 12 describe the identification of targets in bacteria (chapter 11) and eukaryotes using overexpression and knock-down methods as well as target validation for 3’ UTR sites using luciferase reporters (chapter 12). Chapter 13 presents the identification of lncRNAs using computational (like de novo prediction from genomic sequences) and experimental approaches (such as lncRNA specific microarray and RNA immunoprecipitation). Chapter 14 focuses on RNA based regulation in bacteria describing the anti-sense transcription as a main mode of action and the resulting sRNAs are presented as components of regulatory circuits. The methods part concludes with the in depth description of microregulators from stem cells (chapter 15). This chapter focusses on the better understood class of microRNAs which are, in this context, linked to significant epigenetic regulation. The third part of the book, “Applications”, focusses on sRNAs in biological systems. Chapter 16 presents the unique opportunity to silence cancer causing stem cells at a post transcriptional level using sRNAs. The authors also explore RNAi therapy against multi drug resistance genes in a state of art description of the field. Chapter 17 focusses on another aspect of stem cells and the role of microRNAs, microRNA mimics, microRNA antagonists, antisense RNA and siRNA on cell differentiation and regenerative medicine. This direction is continued in chapter 18 where the authors present the role of microRNAs in neurodegenerative diseases focussing on genomic scale analysis of conditions such as Alzheimer’s disease and other dementias. Next, chapter 19 comes as a summary and state of art of siRNA therapeutic design aimed at improving intracellular interactions with RNAi proteins. The section is concluded with two chapters on microRNAs. Chapter 20 focusses on artificial microRNAs and chapter 21 presents an overview of microRNAs involved in cancer. The book represents a valuable collection of articles that reflect the current knowledge in the RNAi field. It is useful for both biologists and bioinformaticians, researchers and students alike, and strengthens the links between molecular biology and bioinformatics.
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