ReviewUnderstanding the mechanistic insight of arsenic exposure and decoding the histone cipher
Graphical abstract
Introduction
Chromatin contains information that encodes the basic components to build-up an organism as a whole. With nearly 3.2 × 109 nucleotides making up the DNA content in the nucleus of each human cell alone (Brown, 2002), it is a massive factory of molecules that regulate required functions within the cell: metabolism, transport, cell division, repair, etc. Approximately 147 base pairs of DNA wrap around the histone octamer core composed of canonical histone proteins and their variants (Cosgrove and Wolberger, 2005). Approximately 20,000 genes are actively transcribed from the human genome, which accounts for 3300 mega base-pairs according to the recently updated database (GRCh38.p12, NCBI). Of the largest chromosomes, hChr-1 (human chromosome-1) has approximately 2000 protein-coding genes while the smallest hChr-Y has approximately 71 identified protein-coding genes; the hChr-19 is almost 1/4th time smaller than hChr-1, yet it has 1500 protein-coding genes. Thus, the size of a chromosome might not be positively correlated with the total number of genes that it can house and hence, it is possible that a highly orchestrated and stratified mechanism exists within this chromatin micro-environment for regulation of gene expression within the cell. In a very recent study, using single cell Hi-C, the authors showed how the chromatin compartmentalizes into an active and in-active segment, the former being closer to the nuclear membrane (Stevens et al., 2017). Accessibility to the chromatin to the interacting molecules (transcription factors, polymerases, ATP dependent chromatin remodeling complexes, etc.) ultimately determines the fate of the cell (Armstrong et al., 2018; Lamparter et al., 2017; Zhou et al., 2016). Further, epigenetic alteration of the histone and the DNA fine-tunes this accessibility. For example, N terminal histone tail plays a critical role in determining the epigenetic profile of a section of chromosome. Specific enzymatic activities chemically modify these tails like acetylation, sumoylation, ribosylation, ubiquitination, and methylation which may increase or decrease the activity of the genomic niche (Xu et al., 2017). To add on to these mechanisms, ATP dependent chromatin remodelers act like motors and identify the characteristic DNA and histone elements within the nucleosomes as well as extra-nucleosomal regions and translocate the nucleosomal core leading to alteration in accessibility of the chromatin (Paul and Bartholomew, 2018; Tyagi et al., 2016).
In this review, we refer to the array of histone post-translational modifications (PTMs) as the histone “code”, encrypting various functions of the cell-like transcriptional regulation, DNA damage repair and replication, progression of the cell cycle and its regulation and developmental processes processes (Cosgrove and Wolberger, 2005; Escargueil et al., 2008; Jenuwein and Allis, 2001; Paquin and Howlett, 2018; Williamson et al., 2012). Different cells have different ways to respond to certain cues within the micro-environment, leading to changes in histone signatures. An ensemble of these histone codes literally forms a “cypher” that are being regularly read by the chromatin-binding proteins that regulate normal as well as abnormal processes within the cells. For example, the change of a stem cell towards a more committed or differentiated form changes the global histone signatures significantly (Corley and Kroll, 2015). Owing to its covalent nature, these modifications are reversible and have been researched for targeted therapeutic strategies. For example, hypo-acetylation of H4 is associated with the breast cancer malignancy while acetylation of H3K9 has been associated with the hepatocellular carcinoma (Suzuki et al., 2009a). This dynamic property of the histone modifying enzymes has attracted much attention from the pharmaceutical companies in recent years (Liu et al., 2006; Oh et al., 2015; Rahman and Grundy, 2011). Unfortunately, not much is known about arsenic-induced alterations in theese post-translational modifications, although chronic exposure to arsenic affects nearly 150 million people in about 70 countries with ever increasing evidence of cancerous outcomes (Ahsan et al., 2006; Garcia-Esquinas et al., 2013; Mendez et al., 2017).
Arsenic, a classified group 1 carcinogenic metalloid, enters our system through environmental exposure (drinking water, dietary and/or occupational sources) leading to a plethora of human health disorders in the exposed population across the globe (WHO, 2010). A number of comprehensive reviews have described the mode of genotoxicity of arsenicosis: The major pathways identified are those involved in DNA damage repair pathway, cell cycle checkpoint regulators, oxidative stress mediators including nuclear and mitochondrial counterparts, etc. (Argos, 2015; Bhattacharjee et al., 2016, 2013a). In order to delineate the of role histone PTMs as a susceptibility factor and/or causal factor in arsenic toxicity, we have restricted our search on these major pathways: transcriptional regulation, oxidative stress, DNA damage repair pathway, and cell cycle check point regulators. Relevant search was conducted using keywords like “arsenic-induced histone post-translational modifications”, “transcriptional regulation”, “DNA damage”, “cell cycle check point regulators”, and “oxidative stress”. In this review, we will describe what is known about arsenic-induced toxicity but will focus mainly on the potential of identifying histone modifications as epigenetic biomarkers and on how epigenetic code alters with arsenic exposure.
Section snippets
Arsenic exposure: mobilization, accessibility and effects
Arsenic is abundant in various geographical hotspots. The exposure hotspots include countries or parts of countries such as Ganga Brahmaputra basin in Eastern India, Bangladesh, parts of China, Vietnam, Thailand, Argentina, and the United States of America. By definition, Group 1 carcinogen is such agent that has sufficient experimental evidence in animals and strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity (IARC Monographs, 2019). Arsenic
Role of histone PTMs in arsenic-induced transcriptional regulation
The histone PTMs regulate the expression of a particular gene, which is cell-specific and can regulate the accessibility of the chromatin depending on the environmental cues. The transcription factors and RNA polymerases need an easy passage to anchor to the DNA backbone before transcribing the RNA. Certain histone PTMs have been associated with either actively transcribed gene promoters, enhancers, or inactive gene promoters. For example, H3K4me1/me3 are well characterized PTMs present at
Epigenetic signature as a potential diagnostic tool and future research prospects
Effective, accurate methods of early detection and clinical diagnosis are urgently required for risk assessment at the treatable stage since the hallmarks of arsenic toxicity develop after a long period of latency (more than 10 years) and 80-85% individuals in a population do not develop any phenotypic manifestation of these symptoms when exposed to arsenic (Ghosh et al., 2006). Emerging number of reports point toward the potential role of circulating cell-free nucleosomes (ccfn) and cell-free
Author contribution
P.B and Dr. P.B. conceived the idea, performed literature review and prepared the tables. P.B, S.P and Dr. P.B. wrote the manuscript. P.B and S.P prepared the figures.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgement
We thankfully acknowledge Dr. Kestas G. Bendinskas, Professor of Biochemistry, Department of Chemistry, SUNY- Oswego, for reviewing and carefully editing our manuscript.
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