Epigenetics Recording Varied Environment and Complex Cell Events Is an Origin of 1 Cellular Aging 2 Xuejun Guo1*, Dong Yang2, X
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1 Epigenetics Recording Varied Environment and Complex Cell Events is an Origin of 2 Cellular Aging 3 Xuejun Guo1*, Dong Yang2, Xiangyuan Zhang1 4 5 1. State Key Laboratory of Environment Simulation, School of Environment, Beijing Normal 6 University, No. 19 Xinjiekouwai Street, Beijing 100875, China 7 2. Gene Engineering and Biotechnology Beijing Key Laboratory 8 College of Life Sciences, Beijing Normal University, No. 19 Xinjiekouwai Street, Beijing, 100875 9 China 10 *Corresponding author: 11 Xuejun Guo 12 Tel: 86-10-5880-7808 13 Fax: 86-10-5880-7808 14 Email: [email protected] 15 16 17 18 19 20 21 22 23 Abstract Although the phenomenal relationship between epigenetics and aging phenotypic 24 changes is built up, an intrinsic connection between the epigenetics and aging requires to be 25 theoretically illuminated. In this study, we propose epigenetic recording of varied cell environment 26 and complex history could be an origin of cellular aging. Through epigenetic modifications, the 27 environment and historical events can induce the chromatin template into activated or repressive 28 accessible structure, thereby shaping the DNA template into a spectrum of chromatin states. The 29 inner nature of diversity and conflicts born by cell environment and its historical events are hence 30 recorded into the chromatin template. This could result in a dissipated spectrum of chromatin state 31 and chaos of overall gene expressions. An unavoidable degradation of epigenome entropy, similar 32 to Shannon entropy, would be consequently induced. The resulted disorder in epigenome, 33 characterized by corrosion of epigenome entropy as reflected in chromatin template, can be stably 34 memorized and propagated through cell divisions. Furthermore, hysteresis nature of epigenetics 35 responding to emerging environment could exacerbate the degradation of epigenome entropy. 36 Besides stochastic errors, we propose that epigenetics disorder and chaos derived from unordered 37 environment and complex cell experiences play an essential role in epigenetic drift and the 38 as-resulted cellular aging. 39 Keywords: Epigenetics; Environment; Cell events; Cellular aging; Epigenome entropy; DNA 40 methylation 41 1. Introduction. 42 Aging is the process of life becoming older characterized by debilitating losses of tissue or 43 cellular function. It refers to irreversible, progressive, and deleterious syndrome of changes that 44 occurs at molecular, cellular, tissue, and organismal levels (Johnson et al., 1999; Campisi, 2013). 45 The causes of aging can be assigned to all kinds of damage, which cause biological systems to fail. 46 These damages may be induced by toxic and nontoxic garbage accumulation, such as protein 47 cross-linking and aggregation, advanced glycation endproducts (AGEs), atherosclerotic and 48 amyloid plaques, inflammatory cytokines, lipofuscin, cortisol, metals, DDT, PCBs, etc 49 (Koschinsky, 1997). They are also derived from metabolic damage (i.e., free radicals, glycation), 50 telomere shortening, decline and inadequate antioxidant defense, defective cell cycle control, 51 declining efficiency of proteasomes, lysosomes, and heat shock proteins (Reiter, 2000; Yan, 1997). 52 Epigenetics refers to heritable changes in gene activity and expression without alterations in 53 the DNA sequence (Allis et al., 2015). Today, stable and long-term but not necessarily heritable 54 alterations in the transcriptional potential of a cell are also assigned to epigenetics (Calvanese et 55 al., 2009). Indexing the genome and potentiate signals from the environment, the chromatin in 56 eukaryotic organisms can be viewed as a dynamic polymer. This chromatin template is modified 57 by a variety of covalent and non-covalent modification. These modification processes include 58 post-translational histone modifications, chromatin-remodeling steps mobilizing or altering 59 nucleosome structures, the dynamic shuffling of histone variants, and the targeting role of small 60 ncRNAs. DNA itself can also be methylated usually at the cytosine residue of CpG dinucleotides 61 (Allis et al., 2015). All these mechanisms provide a set of interrelated pathways regulating the 62 accessibility of the chromatin template to the transcriptional machinery and ultimately determine 63 which genes are expressed and which are not (Pirrotta, 2015). These different patterns of gene 64 expression and silencing may be heritable through cell division and collectively contribute to 65 cellular phenotype (Allis et al., 2015). 66 Epigenetics has emerged as an important subject area in aging biology (Calvanese et al., 2009; 67 Huidobro et al., 2013; Horvath, 2013; Brunet and Berger, 2014; Lardenoije, 2015). The 68 phenomenal relationship between epigenetic drift, a gradual change away from baseline, and age 69 was proposed many years ago (Martin, 2005; Teschendorff et al., 2013; Issa, 2014). The 70 mechanism of epigenetic drift is generally ascribed to stochastic errors and imperfect fidelity in 71 maintenance of epigenetic marks. It is proposed that the fidelity of transmission of epigenetic 72 patterns is variable across the genome (Issa, 2014). Epigenetic drift is related to many of the aging 73 phenotypic changes. For example, genomic global DNA methylation decreases with age 74 (Berdyshev et al., 1967), whereas a number of specific loci become hyper-methylated during aging 75 (Oakes et al., 2003). Other important epigenetic factors, such as histone modifications, also change 76 during aging (Narita et al., 2003). Although the phenomenal relationship between epigenetic drift 77 and aging phenotypic changes are built up, the intrinsic nature of epigenetics causing cellular 78 aging and ultimately the organism aging is not yet fully elucidated. An intrinsic connection 79 between the epigenetics and aging requires to be theoretically illuminated. 80 Epigenetics mediates the relationship between the genome and the environment (Toyokawa 81 et al., 2012; Cooney, 2007; Robert et al.,2011; Sutherland and Costa, 2003; Steves et al., 2012). In 82 fact, human being is started with a fertilized egg with a single genome. Accommodating a plethora 83 of environmental signals, intrinsic and external stimuli, genome is epigenetically programmed to 84 hundreds of different types of cells with a remarkable multitude of distinct phenotypes (Aguilera 85 et al., 2010; Allis et al., 2015). Epigenetics responses and records all the cell environment and 86 events, including all types of environmental signals and changes, and a wide variety of intrinsic 87 and external stimuli (Baccarelli and Bollati, 2009; Sutherland and Costa, 2003; Barros and 88 Offenbacher, 2009; Feil and Fraga, 2012). Here we present a theoretical assay how epigenetics, 89 which stands at the crossroads of genetics and environment, is essentially related to aging. With 90 respect to the basic relationship between epigenetics and environment, we aimed to explain why 91 epigenetics will inevitably and ultimately cause aging, a long-standing mystery. 92 93 2. Environment and cell events may induce the opening or closing of chromatin template 94 through epigenetic modifications, thereby shaping the DNA template into a spectrum of 95 chromatin states. 96 We first depict how environmental cues and cell (i.e., transcriptional) events induce an 97 opening state of the chromatin template through epigenetic modifications. When an environmental 98 signal (external or internal) causes a specific transcriptional event (Alterts et al., 2008), the 99 initiated transcriptional event can concomitantly induce the underlying chromatin template from a 100 native state to an active and open state (Cavalli and Paro, 1999; Struhl, 1998). Responding to 101 environmental cues and transcriptional events, a number of dynamic and elaborate epigenetic 102 mechanisms combine together and interact closely to bring about an opening state of chromatin. 103 This process is accompanied by a series of activated epigenetic modifications, including histone 104 modifications, nucleosome remodeling and the replacement of core histones with histone variants 105 (Allis et al., 2015). An example of activated modification is histone acetylation, which is proposed 106 to neutralize the positive charges of highly basic histone tails and generate a localized expansion 107 of the chromatin fiber, thereby enabling better access of the transcription machinery to the DNA 108 double helix (Hong et al.1993). Histone acetylation is closely associated with the Pol II machinery, 109 thereby providing a simple mechanism to account for the general correlation between 110 transcriptional events and histone acetylation (Struhl, 1998). Onset of transcription, RNA II 111 polymerase may recruit specific KMTs (histone-modifying enzymes) to set some specific histone 112 methylations, such as H3K4me3 around the transcriptional start site and H3K36me3 within the 113 coding sequences (Sims et al., 2004; Smith and Shilatifard, 2013). Such histone modifications in 114 place are often represented as transcriptionally active chromatin (Sims et al., 2007). They are also 115 read by subunits of nucleosome remodeling complex, inducing the recruitment of nucleosome 116 remodeling machines and resulting in looping, twisting, and sliding of nucleosomes (Wysocka et 117 al., 2006). In concert with activated histone modifications, these nucleosome remodeling 118 mechanisms are particularly important for chromatin opening. Finally, the replacement of specific 119 core histones with histone variants may further facilitate