AIR POLLUTION – MONITORING MODELLING AND HEALTH

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320 Air Pollution – Monitoring, Modelling and Health located within CpG-islands that constitute the promoter region of genes. If methylation takes place at these sites, it mostly shuts down the corresponding genes. (Esteller 2002) In case of hyper-methylation of promoter regions – as often encountered in tumor suppressor genes – a permanent shut down of these regions is the obvious result, which causes the affected cell to degenerate or mutate into pre-cancerogenous conditions. (Yang et al., 2005) Another crucial epigenetic mechanism concerns histone-modification and addresses the dense packing of the DNA-filament. If stretched out, the DNA of a cell would cover at least two meters in total length. Supercoiling of the filament enables its packing into a cell nucleus of 10 to 100 μm in diameter. Such packing is achieved via small basic proteins, termed histone cores. Some 147 base-pairs wrap around a histone-octamer, which consists of two H2A/H2B-dimers as well as a H3/H4-tetramer. (Luger et al., 1997) This protein-DNA-unit is known as a nucleosome. Upon DNA-attachment of the linking histone H1, supercoiling occurs in a cascading manner until chromatin is present in its most condensed form: the chromosome (Figure 8). Epigenetics on the histone-level affects the N-terminal tails that protrude from the histone-octamer (see Figure 8). In particular, this regards the basic amino acids lysine and arginine but also serine and threonine. Histone-modifying enzymes append or dislodge specific amino acids. These modifications include methyl-, acetyl- and phosphoryl-groups as well as larger molecules, such as ubiquitin or ADP-ribose. (Biel et al., 2005) In analogy to the genetic code, one refers here to the histone code, as modifications of the basic histone proteins convey specific information. (Strahl & Allis, 2004) Modification of the N- terminal tails loosen the chromatin’s density that enables genes to be readily accessible and transcribed. The opposite effect regards densification of the chromatin and concomitant inhibition of gene readability. In addition to the aforementioned modifications, there are also numerous non-histone proteins that can be biochemically modified, likewise yielding de- or activation of corresponding genes. This regards in particular the tumor-suppressor protein p53, which can be deactivated through deacetylation of histone deacetylase-1 (HDAC1). (Luo et al., 2000) Furthermore, a surprisingly large number of RNAs neither functions as messenger, transfer or ribosomal RNAs, and are thus called non-coding RNAs (ncRNAs). Such RNAs regulate gene expression on various levels, including chromatin modification, transcription, RNA modification, RNA splicing, RNA stability and translation. Among them, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are most prominent. Both regulate gene expression through the RNA interference (RNAi) pathway. More than 1% of predicted genes in higher eukaryotic genomes and up to 30% of protein-encoding genes are assumed to be subjected to miRNA regulation. In addition, miRNAs cooperate with transcription factors (TFs) to control gene expression. (Yu, 2007) Although all cell types within an organism share identical genetic material, they perform different tasks. Task sharing requires a cell-specific readout of genes, which is realized by biochemical markers. Here, epigenetics controls the fate of progeny cells after mitotic division. i.e. lung specific stem cells yield differentiated lung cells although their genome would potentially enable differentiation into any kind of cell. This kind of cellular memory requires to be passed on to the progeny cells. Thus, cellular “learning” predominantly occurs in two ways: either via “bookmarking” or via “paramutation”.(Hollick et al., 1997, Sarge & Park- Sarge, 2005) While the former regards cellular regeneration during the fetal stage all the way through the adulthood, the latter is a characteristic feature for the embryonic phase.
Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics 321 2.2 Adult epigenome Bookmarking transmits cellular memory (i.e. patterns of cellular gene expression) via mitosis to somatic progeny cells of the same type. Throughout one’s lifespan, tissue-specific stem cells are responsible for the development and regeneration of entire organs, such as skin, lung, gut, blood system, etc. In order to meet this task, these stem cells, besides revealing an extensive self-renewal potential, encompass also pluripotency. These properties give rise to all cell types of an organ that differentiate to multipotent progenitors with gradually restricted developmental potential. These progenitors subsequently undergo commitment to one of several lineages and then differentiate along the selected pathway into a functionally specialized cell type of that organ. (Fisher, 2002) In other words, stem cells and resulting progenitors as well as specialized tissue cells share the same genome. Yet, the lower the ranking within cellular ontogenesis, the more genes have to be silenced in order to fulfil the requirements that match organ function. Practically, a healthy somatic epithelial lung stem-cell divides to yield a progeny cell that becomes epigenetically tagged in such a way as to provide a specialized cell. This differentiated cell becomes part of the cellular consortium that constitutes an ensemble yielding the lung with all its physiological functions. Under normal physiological conditions, it would be senseless to differentiate into a cell linage other than e.g. specialized epithelial lung cells. This kind of epigenetic tagging (e.g. epithelial lung cell-linage) is stable and heritable such that a mitotically dividing cellular system gives rise to more cells that correspond to the overall phenotype. (Tost, 2008) Studies based on monozygotic twins with similar epigenomes during early years of life revealed remarkable differences in methylated DNA and acetylated histones during later stages of life. This underlines the temporal metastability of the epigenome. (Fraga et al., 2005) Now, how is epigenetics related to nano-aerosol exposure? As highlighted in Figure 9, environmental exposure of any kind acts as a modulator to the metastable epigenome. (Anway et al., 2005) Metastability affects responsiveness to oxidative stress (Figure 6) and as such Fig. 9. Potential mechanism linking environmental exposures to epigenetic effects. These effects include DNA methylation, histone codes and miRNA expression. The associated changes modify chromatin organization and condensation, gene expression and ultimately disease risks. (modified after Baccarelli & Bollati, 2009)
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AIR POLLUTION - MONITORING, MODELLI
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Contents Preface IX Chapter 1 Urban
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Preface This book provides a compre
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AIR POLLUTION – MONITORING MODELLING AND HEALTH

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